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Sample records for cell therapy products

  1. Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

    Science.gov (United States)

    Lin, Yi-Chu; Wang, Po-Yu; Tsai, Shih-Chih; Lin, Chien-Liang; Tai, Hsuen-Yung; Lo, Chi-Fang; Wu, Shiow-Ing; Chiang, Yu-Mei; Liu, Li-Ling

    2015-01-01

    Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.

  2. A roadmap for cost-of-goods planning to guide economic production of cell therapy products.

    Science.gov (United States)

    Lipsitz, Yonatan Y; Milligan, William D; Fitzpatrick, Ian; Stalmeijer, Evelien; Farid, Suzanne S; Tan, Kah Yong; Smith, David; Perry, Robert; Carmen, Jessica; Chen, Allen; Mooney, Charles; Fink, John

    2017-12-01

    Cell therapy products are frequently developed and produced without incorporating cost considerations into process development, contributing to prohibitively costly products. Herein we contextualize individual process development decisions within a broad framework for cost-efficient therapeutic manufacturing. This roadmap guides the analysis of cost of goods (COG) arising from tissue procurement, material acquisition, facility operation, production, and storage. We present the specific COG considerations related to each of these elements as identified through a 2013 International Society for Cellular Therapy COG survey, highlighting the differences between autologous and allogeneic products. Planning and accounting for COG at each step in the production process could reduce costs, allowing for more affordable market pricing to improve the long-term viability of the cell therapy product and facilitate broader patient access to novel and transformative cell therapies. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Regulatory Oversight of Cell and Gene Therapy Products in Canada.

    Science.gov (United States)

    Ridgway, Anthony; Agbanyo, Francisca; Wang, Jian; Rosu-Myles, Michael

    2015-01-01

    Health Canada regulates gene therapy products and many cell therapy products as biological drugs under the Canadian Food and Drugs Act and its attendant regulations. Cellular products that meet certain criteria, including minimal manipulation and homologous use, may be subjected to a standards-based approach under the Safety of Human Cells, Tissues and Organs for Transplantation Regulations. The manufacture and clinical testing of cell and gene therapy products (CGTPs) presents many challenges beyond those for protein biologics. Cells cannot be subjected to pathogen removal or inactivation procedures and must frequently be administered shortly after final formulation. Viral vector design and manufacturing control are critically important to overall product quality and linked to safety and efficacy in patients through concerns such as replication competence, vector integration, and vector shedding. In addition, for many CGTPs, the value of nonclinical studies is largely limited to providing proof of concept, and the first meaningful data relating to appropriate dosing, safety parameters, and validity of surrogate or true determinants of efficacy must come from carefully designed clinical trials in patients. Addressing these numerous challenges requires application of various risk mitigation strategies and meeting regulatory expectations specifically adapted to the product types. Regulatory cooperation and harmonisation at an international level are essential for progress in the development and commercialisation of these products. However, particularly in the area of cell therapy, new regulatory paradigms may be needed to harness the benefits of clinical progress in situations where the resources and motivation to pursue a typical drug product approval pathway may be lacking.

  4. Cell therapy medicinal product regulatory framework in Europe and its application for MSC based therapy development

    Directory of Open Access Journals (Sweden)

    Janis eAncans

    2012-08-01

    Full Text Available Advanced therapy medicinal products (ATMPs, including cell therapy products, form a new class of medicines in the European Union. Since ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT has been established at European Medicines Agency (EMA for centralized classification, certification and evaluation procedures, and other ATMP related tasks. Guidance documents, initiatives and interaction platforms are available to make the new framework more accessible for small and medium-sized enterprises, academia, hospitals and foundations. Good understanding of centralised and national components of the regulatory system is required to plan product development. It is in the best interests of cell therapy developers to utilise provided resources starting with the preclinical stage. Whilst there have not been mesenchymal stem cell (MSC based medicine authorisations in the EU, three MSC products have received marketing approval in other regions since 2011. Information provided on regulatory requirements, procedures and initiatives is aimed to facilitate MSC based medicinal product development and authorisation in the EU.

  5. Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development

    Science.gov (United States)

    Ancans, Janis

    2012-01-01

    Advanced therapy medicinal products (ATMPs), including cell therapy products, form a new class of medicines in the European Union. Since the ATMPs are at the forefront of scientific innovation in medicine, specific regulatory framework has been developed for these medicines and implemented from 2009. The Committee for Advanced Therapies (CAT) has been established at the European Medicines Agency (EMA) for centralized classification, certification and evaluation procedures, and other ATMP-related tasks. Guidance documents, initiatives, and interaction platforms are available to make the new framework more accessible for small- and medium-sized enterprises, academia, hospitals, and foundations. Good understanding of the centralized and national components of the regulatory system is required to plan product development. It is in the best interests of the cell therapy developers to utilize the resources provided starting with the pre-clinical stage. Whilst there have been no mesenchymal stem cell (MSC)-based medicine authorizations in the EU, three MSC products have received marketing approval in other regions since 2011. The information provided on the regulatory requirements, procedures, and initiatives is aimed at facilitating MSC-based medicinal product development and authorization in the EU. PMID:22912639

  6. Cell Therapy and Tissue Engineering Products for Chondral Knee Injuries

    Directory of Open Access Journals (Sweden)

    Adriana Flórez Cabrera

    2017-07-01

    Full Text Available The articular cartilage is prone to suffer lesions of different etiology, being the articular cartilage lesions of the knee the most common. Although most conventional treatments reduce symptoms they lead to the production of fibrocartilage, which has different characteristics than the hyaline cartilage of the joint. There are few therapeutic approaches that promote the replacement of damaged tissue by functional hyaline cartilage. Among them are the so-called advanced therapies, which use cells and tissue engineering products to promote cartilage regeneration. Most of them are based on scaffolds made of different biomaterials, which seeded or not with endogenous or exogenous cells, can be used as cartilage artificial replacement to improve joint function. This paper reviews some therapeutic approaches focused on the regeneration of articular cartilage of the knee and the biomaterials used to develop scaffolds for cell therapy and tissue engineering of cartilage.

  7. Technological progress and challenges towards cGMP manufacturing of human pluripotent stem cells based therapeutic products for allogeneic and autologous cell therapies.

    Science.gov (United States)

    Abbasalizadeh, Saeed; Baharvand, Hossein

    2013-12-01

    Recent technological advances in the generation, characterization, and bioprocessing of human pluripotent stem cells (hPSCs) have created new hope for their use as a source for production of cell-based therapeutic products. To date, a few clinical trials that have used therapeutic cells derived from hESCs have been approved by the Food and Drug Administration (FDA), but numerous new hPSC-based cell therapy products are under various stages of development in cell therapy-specialized companies and their future market is estimated to be very promising. However, the multitude of critical challenges regarding different aspects of hPSC-based therapeutic product manufacturing and their therapies have made progress for the introduction of new products and clinical applications very slow. These challenges include scientific, technological, clinical, policy, and financial aspects. The technological aspects of manufacturing hPSC-based therapeutic products for allogeneic and autologous cell therapies according to good manufacturing practice (cGMP) quality requirements is one of the most important challenging and emerging topics in the development of new hPSCs for clinical use. In this review, we describe main critical challenges and highlight a series of technological advances in all aspects of hPSC-based therapeutic product manufacturing including clinical grade cell line development, large-scale banking, upstream processing, downstream processing, and quality assessment of final cell therapeutic products that have brought hPSCs closer to clinical application and commercial cGMP manufacturing. © 2013.

  8. From discovery to approval of an advanced therapy medicinal product-containing stem cells, in the EU.

    Science.gov (United States)

    Pellegrini, Graziella; Lambiase, Alessandro; Macaluso, Claudio; Pocobelli, Augusto; Deng, Sophie; Cavallini, Gian Maria; Esteki, Roza; Rama, Paolo

    2016-06-01

    In 1997, the human corneal epithelium was reconstructed in vitro and transplanted on patients. Later, it became a routine treatment, before regulations considered advanced therapy medicinal products and drugs on the same lines. Manufacturing, before and after good manufacturing practice setting, was established in different facilities and the clinical application in several hospitals. Advanced therapy medicinal products, including stem cells, are unique products with different challenges than other drugs: some uncertainties, in addition to benefit, cannot be avoided. This review will focus on all recent developments in the stem cell-based corneal therapy.

  9. Antitumor potential induction and free radicals production in melanoma cells by Boron Neutron Capture Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Faiao-Flores, F. [Biochemical and Biophysical Laboratory, Butantan Institute, 1500 Vital Brasil Avenue, Sao Paulo (Brazil)] [Faculty of Medicine, University of Sao Paulo, 455 Doutor Arnaldo Avenue, Sao Paulo (Brazil); Coelho, P.R.P.; Muniz, R.O.R.; Souza, G.S. [Institute for Nuclear and Energy Research, 2242 Lineu Prestes Avenue, Sao Paulo (Brazil); Arruda-Neto, J. [Physics Institute, University of Sao Paulo, 187 Matao Street, Sao Paulo (Brazil)] [FESP, Sao Paulo Engineering School, 5520 Nove de Julho Avenue, Sao Paulo (Brazil); Maria, Durvanei A., E-mail: durvaneiaugusto@yahoo.com.br [Biochemical and Biophysical Laboratory, Butantan Institute, 1500 Vital Brasil Avenue, Sao Paulo (Brazil)

    2011-12-15

    Antiproliferative and oxidative damage effects occurring in Boron Neutron Capture Therapy (BNCT) in normal fibroblasts and melanoma cell lines were analyzed. Melanoma cells and normal fibroblasts were treated with different concentrations of Boronophenylalanine and irradiated with thermal neutron flux. The cellular viability and the oxidative stress were determined. BNCT induced free radicals production and proliferative potential inhibition in melanoma cells. Therefore, this therapeutic technique could be considered efficient to inhibit growth of melanoma with minimal effects on normal tissues. - Highlights: Black-Right-Pointing-Pointer Boron Neutron Capture Therapy (BNCT) induces melanoma cell death. Black-Right-Pointing-Pointer BNCT stimulates free radicals production and proliferative inhibition in melanoma cells. Black-Right-Pointing-Pointer It produces tumor membrane degeneration and destruction with apoptotic bodies formation. Black-Right-Pointing-Pointer This therapy damages tumor cells selectively, with minimum effects on normal adjacent tissue.

  10. Cell Therapy in Dermatology

    Science.gov (United States)

    Petrof, Gabriela; Abdul-Wahab, Alya; McGrath, John A.

    2014-01-01

    Harnessing the regenerative capacity of keratinocytes and fibroblasts from human skin has created new opportunities to develop cell-based therapies for patients. Cultured cells and bioengineered skin products are being used to treat patients with inherited and acquired skin disorders associated with defective skin, and further clinical trials of new products are in progress. The capacity of extracutaneous sources of cells such as bone marrow is also being investigated for its plasticity in regenerating skin, and new strategies, such as the derivation of inducible pluripotent stem cells, also hold great promise for future cell therapies in dermatology. This article reviews some of the preclinical and clinical studies and future directions relating to cell therapy in dermatology, particularly for inherited skin diseases associated with fragile skin and poor wound healing. PMID:24890834

  11. Improving the Safety of Cell Therapy Products by Suicide Gene Transfer

    Directory of Open Access Journals (Sweden)

    Antonio eDi Stasi

    2014-11-01

    Full Text Available Adoptive T-cell therapy can involve donor lymphocyte infusion (DLI after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte (TILs expanded ex-vivo, or more recently the use of T cell receptor (TCR or chimeric antigen receptor (CAR redirected T cells. However cellular therapies can pose significant risks, including graft-versus-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase (HSV-TK and inducible-caspase-9 (iCasp9.

  12. How we make cell therapy in Italy

    Directory of Open Access Journals (Sweden)

    Montemurro T

    2015-08-01

    Full Text Available Tiziana Montemurro, Mariele Viganò, Silvia Budelli, Elisa Montelatici, Cristiana Lavazza, Luigi Marino, Valentina Parazzi, Lorenza Lazzari, Rosaria GiordanoCell Factory, Unit of Cell Therapy and Cryobiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, ItalyAbstract: In the 21st century scenario, new therapeutic tools are needed to take up the social and medical challenge posed by the more and more frequent degenerative disorders and by the aging of population. The recent category of advanced therapy medicinal products has been created to comprise cellular, gene therapy, and tissue engineered products, as a new class of drugs. Their manufacture requires the same pharmaceutical framework as for conventional drugs and this means that industrial, large-scale manufacturing process has to be adapted to the peculiar characteristics of cell-containing products. Our hospital took up the challenge of this new path in the early 2000s; and herein we describe the approach we followed to set up a pharmaceutical-grade facility in a public hospital context, with the aim to share the solutions we found to make cell therapy compliant with the requirements for the production and the quality control of a high-standard medicinal product.Keywords: advanced therapy medicinal product, good manufacturing practices, stem cells

  13. Biomarkers in T cell therapy clinical trials

    Directory of Open Access Journals (Sweden)

    Kalos Michael

    2011-08-01

    Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.

  14. Nonclinical safety strategies for stem cell therapies

    Energy Technology Data Exchange (ETDEWEB)

    Sharpe, Michaela E., E-mail: michaela_sharpe@yahoo.com [Investigative Toxicology, Drug Safety Research and Development, Pfizer Ltd, Ramsgate Road, Sandwich, CT13 9NJ (United Kingdom); Morton, Daniel [Exploratory Drug Safety, Drug Safety Research and Development, Pfizer Inc, Cambridge, 02140 (United States); Rossi, Annamaria [Investigative Toxicology, Drug Safety Research and Development, Pfizer Ltd, Ramsgate Road, Sandwich, CT13 9NJ (United Kingdom)

    2012-08-01

    Recent breakthroughs in stem cell biology, especially the development of the induced pluripotent stem cell techniques, have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells in regenerative medicine. Stem cell therapies are being considered for the treatment of degenerative diseases, inflammatory conditions, cancer and repair of damaged tissue. The safety of a stem cell therapy depends on many factors including the type of cell therapy, the differentiation status and proliferation capacity of the cells, the route of administration, the intended clinical location, long term survival of the product and/or engraftment, the need for repeated administration, the disease to be treated and the age of the population. Understanding the product profile of the intended therapy is crucial to the development of the nonclinical safety study design.

  15. Nonclinical safety strategies for stem cell therapies

    International Nuclear Information System (INIS)

    Sharpe, Michaela E.; Morton, Daniel; Rossi, Annamaria

    2012-01-01

    Recent breakthroughs in stem cell biology, especially the development of the induced pluripotent stem cell techniques, have generated tremendous enthusiasm and efforts to explore the therapeutic potential of stem cells in regenerative medicine. Stem cell therapies are being considered for the treatment of degenerative diseases, inflammatory conditions, cancer and repair of damaged tissue. The safety of a stem cell therapy depends on many factors including the type of cell therapy, the differentiation status and proliferation capacity of the cells, the route of administration, the intended clinical location, long term survival of the product and/or engraftment, the need for repeated administration, the disease to be treated and the age of the population. Understanding the product profile of the intended therapy is crucial to the development of the nonclinical safety study design.

  16. Entropy production in a cell and reversal of entropy flow as an anticancer therapy

    Institute of Scientific and Technical Information of China (English)

    Liao-fu LUO

    2009-01-01

    The entropy production rate of cancer cells is always higher than healthy cells in the case where no external field is applied. Different entropy production between two kinds of cells determines the direction of entropy flow among cells. The entropy flow is the carrier of information flow. The entropy flow from cancerous cells to healthy cells takes along the harmful information of cancerous cells, propagating its toxic action to healthy tissues. We demonstrate that a low-frequency and low- intensity electromagnetic field or ultrasound irradiation may increase the entropy production rate of a cell in normal tissue than that in cancer and consequently re- verse the direction of entropy current between two kinds of cells. The modification of the PH value of cells may also cause the reversal of the direction of entropy flow between healthy and cancerous cells. Therefore, the bio- logical tissue under the irradiation of an electromagnetic field or ultrasound or under the appropriate change of cell acidity can avoid the propagation of harmful infor- marion from cancer cells. We suggest that this entropy mechanism possibly provides a basis for a novel approach to anticancer therapy.

  17. Automation of cellular therapy product manufacturing: results of a split validation comparing CD34 selection of peripheral blood stem cell apheresis product with a semi-manual vs. an automatic procedure

    OpenAIRE

    H?mmer, Christiane; Poppe, Carolin; Bunos, Milica; Stock, Belinda; Wingenfeld, Eva; Huppert, Volker; Stuth, Juliane; Reck, Kristina; Essl, Mike; Seifried, Erhard; Bonig, Halvard

    2016-01-01

    Background Automation of cell therapy manufacturing promises higher productivity of cell factories, more economical use of highly-trained (and costly) manufacturing staff, facilitation of processes requiring manufacturing steps at inconvenient hours, improved consistency of processing steps and other benefits. One of the most broadly disseminated engineered cell therapy products is immunomagnetically selected CD34+?hematopoietic ?stem? cells (HSCs). Methods As the clinical GMP-compliant autom...

  18. Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Products Successfully to the Market - Report from the CAT-DGTI-GSCN Workshop at the DGTI Annual Meeting 2014.

    Science.gov (United States)

    Celis, Patrick; Ferry, Nicolas; Hystad, Marit; Schüßler-Lenz, Martina; Doevendans, Pieter A; Flory, Egbert; Beuneu, Claire; Reischl, Ilona; Salmikangas, Paula

    2015-05-01

    On September 11, 2014, a workshop entitled 'Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Product Successfully to the Market' was held at the 47th annual meeting of the German Society for Transfusion Medicine and Immunohematology (DGTI), co-organised by the European Medicines Agency (EMA) and the DGTI in collaboration with the German Stem Cell Network (GSCN). The workshop brought together over 160 participants from academia, hospitals, small- or medium-sized enterprise developers and regulators. At the workshop, speakers from EMA, the Committee for Advanced Therapies (CAT), industry and academia addressed the regulatory aspects of development and authorisation of advanced therapy medicinal products (ATMPs), classification of ATMPs and considerations on cell-based therapies for cardiac repair. The open forum discussion session allowed for a direct interaction between ATMP developers and the speakers from EMA and CAT.

  19. Market access pathways for cell therapies in France.

    Science.gov (United States)

    Rémuzat, Cécile; Toumi, Mondher; Jørgensen, Jesper; Kefalas, Panos

    2015-01-01

    Cell therapies can be classified into three main categories of products: advanced therapy medicinal products (ATMPs), ATMPs prepared on a non-routine basis (hospital exemptions), and minimally manipulated cells. Despite the benefits that cell therapies can bring to patients, they are subject to complex pathways to reach the market in France. The objective of this study was to identify and describe routes to market access for cell therapies in France and how these vary by regulatory status. The research was structured following five main steps: (1) identification of the French regulatory framework for cell therapies; (2) identification of the health products categorised as cell therapies in France; (3) mapping of the market access pathways per category of cell therapy; (4) validation of findings by interviewing experts; and (5) development of a roadmap summarising market access pathways for cell therapies in France. The secondary research methodology included a comprehensive literature review conducted on websites of French public health institutions, complemented by a research for peer-reviewed articles, abstracts, and grey literature. Different market access pathways are possible depending on the cell therapy category. For ATMPs, market access pathways depend on the licensing status of the therapy. Licensed ATMPs followed the same market access pathways as 'conventional' pharmaceuticals, whereas not-yet-licensed ATMPs can be funded via a specific financial allowance under the framework of a Temporary Authorisation for Use procedure or various research programmes. For new ATMPs that are associated with a separate medical device (not considered as 'combined ATMPs') or associated with a new medical procedure, additional pathways will apply for the medical device and/or medical procedure to be reimbursed in the ambulatory settings or at hospital. The most likely funding option for ATMPs prepared on a non-routine basis is outside the diagnosis-related group (DRG

  20. Toward precision manufacturing of immunogene T-cell therapies.

    Science.gov (United States)

    Xu, Jun; Melenhorst, J Joseph; Fraietta, Joseph A

    2018-05-01

    Cancer can be effectively targeted using a patient's own T cells equipped with synthetic receptors, including chimeric antigen receptors (CARs) that redirect and reprogram these lymphocytes to mediate tumor rejection. Over the past two decades, several strategies to manufacture genetically engineered T cells have been proposed, with the goal of generating optimally functional cellular products for adoptive transfer. Based on this work, protocols for manufacturing clinical-grade CAR T cells have been established, but these complex methods have been used to treat only a few hundred individuals. As CAR T-cell therapy progresses into later-phase clinical trials and becomes an option for more patients, a major consideration for academic institutions and industry is developing robust manufacturing processes that will permit scaling-out production of immunogene T-cell therapies in a reproducible and efficient manner. In this review, we will discuss the steps involved in cell processing, the major obstacles surrounding T-cell manufacturing platforms and the approaches for improving cellular product potency. Finally, we will address the challenges of expanding CAR T-cell therapy to a global patient population. Copyright © 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  1. Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Products Successfully to the Market – Report from the CAT-DGTI-GSCN Workshop at the DGTI Annual Meeting 2014

    Science.gov (United States)

    Celis, Patrick; Ferry, Nicolas; Hystad, Marit; Schüßler-Lenz, Martina; Doevendans, Pieter A.; Flory, Egbert; Beuneu, Claire; Reischl, Ilona; Salmikangas, Paula

    2015-01-01

    On September 11, 2014, a workshop entitled ‘Advanced Therapy Medicinal Products: How to Bring Cell-Based Medicinal Product Successfully to the Market’ was held at the 47th annual meeting of the German Society for Transfusion Medicine and Immunohematology (DGTI), co-organised by the European Medicines Agency (EMA) and the DGTI in collaboration with the German Stem Cell Network (GSCN). The workshop brought together over 160 participants from academia, hospitals, small- or medium-sized enterprise developers and regulators. At the workshop, speakers from EMA, the Committee for Advanced Therapies (CAT), industry and academia addressed the regulatory aspects of development and authorisation of advanced therapy medicinal products (ATMPs), classification of ATMPs and considerations on cell-based therapies for cardiac repair. The open forum discussion session allowed for a direct interaction between ATMP developers and the speakers from EMA and CAT. PMID:26195933

  2. Characteristics, applications and prospects of mesenchymal stem cells in cell therapy.

    Science.gov (United States)

    Guadix, Juan A; Zugaza, José L; Gálvez-Martín, Patricia

    2017-05-10

    Recent advances in the field of cell therapy and regenerative medicine describe mesenchymal stem cells (MSCs) as potential biological products due to their ability to self-renew and differentiate. MSCs are multipotent adult cells with immunomodulatory and regenerative properties, and, given their therapeutic potential, they are being widely studied in order to evaluate their viability, safety and efficacy. In this review, we describe the main characteristics and cellular sources of MSCs, in addition to providing an overview of their properties and current clinical applications, as well offering updated information on the regulatory aspects that define them as somatic cell therapy products. Cell therapy based on MSCs is offered nowadays as a pharmacological alternative, although there are still challenges to be addressed in this regard. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  3. Cell therapy worldwide: an incipient revolution.

    Science.gov (United States)

    Rao, Mahendra; Mason, Chris; Solomon, Susan

    2015-01-01

    The regenerative medicine field is large, diverse and active worldwide. A variety of different organizational and product models have been successful, and pioneering entrepreneurs have shown both what can work and, critically, what does not. Evolving regulations, novel funding mechanisms combined with new technological breakthroughs are keeping the field in a state of flux. The field struggles to cope with the lack of infrastructure and investment, it nevertheless has evolved from its roots in human stem cell therapy and tissue and organ transplants to a field composed of a variety of products from multiple cell sources with approval for use in numerous countries. Currently, tens of thousands of patients have been treated with some kind of cell therapy.

  4. How we make cell therapy in Italy.

    Science.gov (United States)

    Montemurro, Tiziana; Viganò, Mariele; Budelli, Silvia; Montelatici, Elisa; Lavazza, Cristiana; Marino, Luigi; Parazzi, Valentina; Lazzari, Lorenza; Giordano, Rosaria

    2015-01-01

    In the 21st century scenario, new therapeutic tools are needed to take up the social and medical challenge posed by the more and more frequent degenerative disorders and by the aging of population. The recent category of advanced therapy medicinal products has been created to comprise cellular, gene therapy, and tissue engineered products, as a new class of drugs. Their manufacture requires the same pharmaceutical framework as for conventional drugs and this means that industrial, large-scale manufacturing process has to be adapted to the peculiar characteristics of cell-containing products. Our hospital took up the challenge of this new path in the early 2000s; and herein we describe the approach we followed to set up a pharmaceutical-grade facility in a public hospital context, with the aim to share the solutions we found to make cell therapy compliant with the requirements for the production and the quality control of a high-standard medicinal product.

  5. European regulatory tools for advanced therapy medicinal products.

    Science.gov (United States)

    Flory, Egbert; Reinhardt, Jens

    2013-12-01

    Increasing scientific knowledge and technical innovations in the areas of cell biology, biotechnology and medicine resulted in the development of promising therapeutic approaches for the prevention and treatment of human diseases. Advanced therapy medicinal products (ATMPs) reflect a complex and innovative class of biopharmaceuticals as these products are highly research-driven, characterised by innovative manufacturing processes and heterogeneous with regard to their origin, type and complexity. This class of ATMP integrates gene therapy medicinal products, somatic cell therapy medicinal products and tissue engineering products and are often individualized and patient-specific products. Multiple challenges arise from the nature of ATMPs, which are often developed by micro, small and medium sized enterprises, university and academia, for whom regulatory experiences are limited and regulatory requirements are challenging. Regulatory guidance such as the reflection paper on classification of ATMPs and guidelines highlighting product-specific issues support academic research groups and pharmaceutical companies to foster the development of safe and effective ATMPs. This review provides an overview on the European regulatory aspects of ATMPs and highlights specific regulatory tools such as the ATMP classification procedure, a discussion on the hospital exemption for selected ATMPs as well as borderline issues towards transplants/transfusion products.

  6. Advanced therapy medicinal products: current and future perspectives.

    Science.gov (United States)

    Hanna, Eve; Rémuzat, Cécile; Auquier, Pascal; Toumi, Mondher

    2016-01-01

    Advanced therapy medicinal products (ATMPs) are innovative therapies that encompass gene therapy, somatic cell therapy, and tissue-engineered products. These therapies are expected to bring important health benefits, but also to substantially impact the pharmaceuticals budget. The aim of this study was to characterise the ATMPs in development and discuss future implications in terms of market access. Clinical trials were searched in the following databases: EudraCT (EU Drug Regulating Authorities Clinical Trials), ClinicalTrials.gov, and ICTRP (International Clinical Trials Registry Platform of the World Health Organization). Trials were classified by category of ATMP as defined by European regulation EC No. 1394/2007, as well as by development phase and disease area. The database search identified 939 clinical trials investigating ATMPs (85% ongoing, 15% completed). The majority of trials were in the early stages (Phase I, I/II: 64.3%, Phase II, II/III: 27.9%, Phase 3: 6.9%). Per category of ATMP, we identified 53.6% of trials for somatic cell therapies, 22.8% for tissue-engineered products, 22.4% for gene therapies, and 1.2% for combined products (incorporating a medical device). Disease areas included cancer (24.8%), cardiovascular diseases (19.4%), musculoskeletal (10.5%), immune system and inflammation (11.5%), neurology (9.1%), and others. Of the trials, 47.2% enrolled fewer than 25 patients. Due to the complexity and specificity of ATMPs, new clinical trial methodologies are being considered (e.g., small sample size, non-randomised trials, single-arm trials, surrogate endpoints, integrated protocols, and adaptive designs). Evidence generation post-launch will become unavoidable to address payers' expectations. ATMPs represent a fast-growing field of interest. Although most of the products are in an early development phase, the combined trial phase and the potential to cure severe chronic conditions suggest that ATMPs may reach the market earlier than

  7. Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy.

    Science.gov (United States)

    Gao, Yuanzheng; Guo, Xiuming; Santostefano, Katherine; Wang, Yanlin; Reid, Tammy; Zeng, Desmond; Terada, Naohiro; Ashizawa, Tetsuo; Xia, Guangbin

    2016-08-01

    Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

  8. Counter-flow elutriation of clinical peripheral blood mononuclear cell concentrates for the production of dendritic and T cell therapies.

    Science.gov (United States)

    Stroncek, David F; Fellowes, Vicki; Pham, Chauha; Khuu, Hanh; Fowler, Daniel H; Wood, Lauren V; Sabatino, Marianna

    2014-09-17

    Peripheral blood mononuclear cells (PBMC) concentrates collected by apheresis are frequently used as starting material for cellular therapies, but the cell of interest must often be isolated prior to initiating manufacturing. The results of enriching 59 clinical PBMC concentrates for monocytes or lymphocytes from patients with solid tumors or multiple myeloma using a commercial closed system semi-automated counter-flow elutriation instrument (Elutra, Terumo BCT) were evaluated for quality and consistency. Elutriated monocytes (n = 35) were used to manufacture autologous dendritic cells and elutriated lymphocytes (n = 24) were used manufacture autologous T cell therapies. Elutriated monocytes with >10% neutrophils were subjected to density gradient sedimentation to reduce neutrophil contamination and elutriated lymphocytes to RBC lysis. Elutriation separated the PBMC concentrates into 5 fractions. Almost all of the lymphocytes, platelets and red cells were found in fractions 1 and 2; in contrast, most of the monocytes, 88.6 ± 43.0%, and neutrophils, 74.8 ± 64.3%, were in fraction 5. In addition, elutriation of 6 PBMCs resulted in relatively large quantities of monocytes in fractions 1 or 2. These 6 PBMCs contained greater quantities of monocytes than the other 53 PBMCs. Among fraction 5 isolates 38 of 59 contained >10% neutrophils. High neutrophil content of fraction 5 was associated with greater quantities of neutrophils in the PBMC concentrate. Following density gradient separation the neutrophil counts fell to 3.6 ± 3.4% (all products contained <10% neutrophils). Following red cell lysis of the elutriated lymphocyte fraction the lymphocyte recovery was 86.7 ± 24.0% and 34.3 ± 37.4% of red blood cells remained. Elutriation was consistent and effective for isolating monocytes and lymphocytes from PBMC concentrates for manufacturing clinical cell therapies, but further processing is often required.

  9. The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis

    DEFF Research Database (Denmark)

    Hedegaard, Chris J; Krakauer, Martin; Bendtzen, Klaus

    2008-01-01

    Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein...... (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p...

  10. Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager.

    Science.gov (United States)

    Wing, Anna; Fajardo, Carlos Alberto; Posey, Avery D; Shaw, Carolyn; Da, Tong; Young, Regina M; Alemany, Ramon; June, Carl H; Guedan, Sonia

    2018-05-01

    T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR . ©2018 American Association for Cancer Research.

  11. [Prerequisite for hematopoietic cellular therapy programs to set up chimeric antigen receptor T-cell therapy (CAR T-cells): Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

    Science.gov (United States)

    Yakoub-Agha, Ibrahim; Ferrand, Christophe; Chalandon, Yves; Ballot, Caroline; Castilla Llorente, Cristina; Deschamps, Marina; Gauthier, Jordan; Labalette, Myriam; Larghero, Jérôme; Maheux, Camille; Moreau, Anne-Sophie; Varlet, Pauline; Pétillon, Marie-Odile; Pinturaud, Marine; Rubio, Marie Thérèse; Chabannon, Christian

    2017-12-01

    CAR T-cells are autologous or allogeneic human lymphocytes that are genetically engineered to express a chimeric antigen receptor targeting an antigen expressed on tumor cells such as CD19. CAR T-cells represent a new class of medicinal products, and belong to the broad category of Advanced Therapy Medicinal Products (ATMPs), as defined by EC Regulation 2007-1394. Specifically, they are categorized as gene therapy medicinal products. Although CAR T-cells are cellular therapies, the organization for manufacturing and delivery is far different from the one used to deliver hematopoietic cell grafts, for different reasons including their classification as medicinal products. Currently available clinical observations were mostly produced in the context of trials conducted either in the USA or in China. They demonstrate remarkable efficacy for patients presenting advanced or poor-prognosis hematological malignancies, however with severe side effects in a significant proportion of patients. Toxicities can and must be anticipated and dealt with in the context of a full coordination between the clinical cell therapy ward in charge of the patient, and the neighboring intensive care unit. The present workshop aimed at identifying prerequisites to be met in order for French hospitals to get efficiently organized and fulfill sponsors' expectations before initiation of clinical trials designed to investigate CAR T-cells. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  12. Microencapsulation of Stem Cells for Therapy.

    Science.gov (United States)

    Leslie, Shirae K; Kinney, Ramsey C; Schwartz, Zvi; Boyan, Barbara D

    2017-01-01

    An increasing demand to regenerate tissues from patient-derived sources has led to the development of cell-based therapies using autologous stem cells, thereby decreasing immune rejection of scaffolds coupled with allogeneic stem cells or allografts. Adult stem cells are multipotent and are readily available in tissues such as fat and bone marrow. They possess the ability to repair and regenerate tissue through the production of therapeutic factors, particularly vasculogenic proteins. A major challenge in cell-based therapies is localizing the delivered stem cells to the target site. Microencapsulation of cells provides a porous polymeric matrix that can provide a protected environment, localize the cells to one area, and maintain their viability by enabling the exchange of nutrients and waste products between the encapsulated cells and the surrounding tissue. In this chapter, we describe a method to produce injectable microbeads containing a tunable number of stem cells using the biopolymer alginate. The microencapsulation process involves extrusion of the alginate suspension containing cells from a microencapsulator, a syringe pump to control its flow rate, an electrostatic potential to overcome capillary forces and a reduced Ca ++ cross-linking solution containing a nutrient osmolyte, to form microbeads. This method allows the encapsulated cells to remain viable up to three weeks in culture and up to three months in vivo and secrete growth factors capable of supporting tissue regeneration.

  13. Regulatory landscape for cell therapy--EU view.

    Science.gov (United States)

    McBlane, James W

    2015-09-01

    This article addresses regulation of cell therapies in the European Union (EU), covering cell sourcing and applications for clinical trials and marketing authorisation applications. Regulatory oversight of cell sourcing and review of applications for clinical trials with cell therapies are handled at national level, that is, separately with each country making its own decisions. For clinical trials, this can lead to different decisions in different countries for the same trial. A regulation is soon to come into force that will address this and introduce a more efficient clinical trial application process. However, at the marketing authorisation stage, the process is pan-national: the Committee for Human Medicinal Products (CHMP) is responsible for giving the final scientific opinion on all EU marketing authorisation applications for cell therapies: favourable scientific opinions are passed to the European Commission (EC) for further consultation and, if successful, grant of a marketing authorisation valid in all 28 EU countries. In its review of applications for marketing authorisations (MAAs) for cell therapies, the CHMP is obliged to consult the Committee for Advanced Therapies (CAT), who conduct detailed scientific assessments of these applications, with assessment by staff from national regulatory authorities and specialist advisors to the regulators. Copyright © 2015.

  14. Gene and cell therapy for children--new medicines, new challenges?

    Science.gov (United States)

    Buckland, Karen F; Bobby Gaspar, H

    2014-06-01

    The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances

  15. Allogeneic cell therapy bioprocess economics and optimization: single-use cell expansion technologies.

    Science.gov (United States)

    Simaria, Ana S; Hassan, Sally; Varadaraju, Hemanthram; Rowley, Jon; Warren, Kim; Vanek, Philip; Farid, Suzanne S

    2014-01-01

    For allogeneic cell therapies to reach their therapeutic potential, challenges related to achieving scalable and robust manufacturing processes will need to be addressed. A particular challenge is producing lot-sizes capable of meeting commercial demands of up to 10(9) cells/dose for large patient numbers due to the current limitations of expansion technologies. This article describes the application of a decisional tool to identify the most cost-effective expansion technologies for different scales of production as well as current gaps in the technology capabilities for allogeneic cell therapy manufacture. The tool integrates bioprocess economics with optimization to assess the economic competitiveness of planar and microcarrier-based cell expansion technologies. Visualization methods were used to identify the production scales where planar technologies will cease to be cost-effective and where microcarrier-based bioreactors become the only option. The tool outputs also predict that for the industry to be sustainable for high demand scenarios, significant increases will likely be needed in the performance capabilities of microcarrier-based systems. These data are presented using a technology S-curve as well as windows of operation to identify the combination of cell productivities and scale of single-use bioreactors required to meet future lot sizes. The modeling insights can be used to identify where future R&D investment should be focused to improve the performance of the most promising technologies so that they become a robust and scalable option that enables the cell therapy industry reach commercially relevant lot sizes. The tool outputs can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes needed as products proceed through the development pathway. © 2013 Wiley Periodicals, Inc.

  16. Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.

    Science.gov (United States)

    D'Amour, Kevin A; Bang, Anne G; Eliazer, Susan; Kelly, Olivia G; Agulnick, Alan D; Smart, Nora G; Moorman, Mark A; Kroon, Evert; Carpenter, Melissa K; Baetge, Emmanuel E

    2006-11-01

    Of paramount importance for the development of cell therapies to treat diabetes is the production of sufficient numbers of pancreatic endocrine cells that function similarly to primary islets. We have developed a differentiation process that converts human embryonic stem (hES) cells to endocrine cells capable of synthesizing the pancreatic hormones insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin. This process mimics in vivo pancreatic organogenesis by directing cells through stages resembling definitive endoderm, gut-tube endoderm, pancreatic endoderm and endocrine precursor--en route to cells that express endocrine hormones. The hES cell-derived insulin-expressing cells have an insulin content approaching that of adult islets. Similar to fetal beta-cells, they release C-peptide in response to multiple secretory stimuli, but only minimally to glucose. Production of these hES cell-derived endocrine cells may represent a critical step in the development of a renewable source of cells for diabetes cell therapy.

  17. Automation of cellular therapy product manufacturing: results of a split validation comparing CD34 selection of peripheral blood stem cell apheresis product with a semi-manual vs. an automatic procedure.

    Science.gov (United States)

    Hümmer, Christiane; Poppe, Carolin; Bunos, Milica; Stock, Belinda; Wingenfeld, Eva; Huppert, Volker; Stuth, Juliane; Reck, Kristina; Essl, Mike; Seifried, Erhard; Bonig, Halvard

    2016-03-16

    Automation of cell therapy manufacturing promises higher productivity of cell factories, more economical use of highly-trained (and costly) manufacturing staff, facilitation of processes requiring manufacturing steps at inconvenient hours, improved consistency of processing steps and other benefits. One of the most broadly disseminated engineered cell therapy products is immunomagnetically selected CD34+ hematopoietic "stem" cells (HSCs). As the clinical GMP-compliant automat CliniMACS Prodigy is being programmed to perform ever more complex sequential manufacturing steps, we developed a CD34+ selection module for comparison with the standard semi-automatic CD34 "normal scale" selection process on CliniMACS Plus, applicable for 600 × 10(6) target cells out of 60 × 10(9) total cells. Three split-validation processings with healthy donor G-CSF-mobilized apheresis products were performed; feasibility, time consumption and product quality were assessed. All processes proceeded uneventfully. Prodigy runs took about 1 h longer than CliniMACS Plus runs, albeit with markedly less hands-on operator time and therefore also suitable for less experienced operators. Recovery of target cells was the same for both technologies. Although impurities, specifically T- and B-cells, were 5 ± 1.6-fold and 4 ± 0.4-fold higher in the Prodigy products (p = ns and p = 0.013 for T and B cell depletion, respectively), T cell contents per kg of a virtual recipient receiving 4 × 10(6) CD34+ cells/kg was below 10 × 10(3)/kg even in the worst Prodigy product and thus more than fivefold below the specification of CD34+ selected mismatched-donor stem cell products. The products' theoretical clinical usability is thus confirmed. This split validation exercise of a relatively short and simple process exemplifies the potential of automatic cell manufacturing. Automation will further gain in attractiveness when applied to more complex processes, requiring frequent interventions or handling at

  18. Regulatory structures for gene therapy medicinal products in the European Union.

    Science.gov (United States)

    Klug, Bettina; Celis, Patrick; Carr, Melanie; Reinhardt, Jens

    2012-01-01

    Taking into account the complexity and technical specificity of advanced therapy medicinal products: (gene and cell therapy medicinal products and tissue engineered products), a dedicated European regulatory framework was needed. Regulation (EC) No. 1394/2007, the "ATMP Regulation" provides tailored regulatory principles for the evaluation and authorization of these innovative medicines. The majority of gene or cell therapy product development is carried out by academia, hospitals, and small- and medium-sized enterprises (SMEs). Thus, acknowledging the particular needs of these types of sponsors, the legislation also provides incentives for product development tailored to them. The European Medicines Agency (EMA) and, in particular, its Committee for Advanced Therapies (CAT) provide a variety of opportunities for early interaction with developers of ATMPs to enable them to have early regulatory and scientific input. An important tool to promote innovation and the development of new medicinal products by micro-, small-, and medium-sized enterprises is the EMA's SME initiative launched in December 2005 to offer financial and administrative assistance to smaller companies. The European legislation also foresees the involvement of stakeholders, such as patient organizations, in the development of new medicines. Considering that gene therapy medicinal products are developed in many cases for treatment of rare diseases often of monogenic origin, the involvement of patient organizations, which focus on rare diseases and genetic and congenital disorders, is fruitful. Two such organizations are represented in the CAT. Research networks play another important role in the development of gene therapy medicinal products. The European Commission is funding such networks through the EU Sixth Framework Program. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. A guide to manufacturing CAR T cell therapies.

    Science.gov (United States)

    Vormittag, Philipp; Gunn, Rebecca; Ghorashian, Sara; Veraitch, Farlan S

    2018-02-17

    In recent years, chimeric antigen receptor (CAR) modified T cells have been used as a treatment for haematological malignancies in several phase I and II trials and with Kymriah of Novartis and Yescarta of KITE Pharma, the first CAR T cell therapy products have been approved. Promising clinical outcomes have yet been tempered by the fact that many therapies may be prohibitively expensive to manufacture. The process is not yet defined, far from being standardised and often requires extensive manual handling steps. For academia, big pharma and contract manufacturers it is difficult to obtain an overview over the process strategies and their respective advantages and disadvantages. This review details current production processes being used for CAR T cells with a particular focus on efficacy, reproducibility, manufacturing costs and release testing. By undertaking a systematic analysis of the manufacture of CAR T cells from reported clinical trial data to date, we have been able to quantify recent trends and track the uptake of new process technology. Delivering new processing options will be key to the success of the CAR-T cells ensuring that excessive manufacturing costs do not disrupt the delivery of exciting new therapies to the wide possible patient cohort. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Towards an advanced therapy medicinal product based on mesenchymal stromal cells isolated from the umbilical cord tissue: quality and safety data.

    Science.gov (United States)

    Martins, José Paulo; Santos, Jorge Miguel; de Almeida, Joana Marto; Filipe, Mariana Alves; de Almeida, Mariana Vargas Teixeira; Almeida, Sílvia Cristina Paiva; Água-Doce, Ana; Varela, Alexandre; Gilljam, Mari; Stellan, Birgitta; Pohl, Susanne; Dittmar, Kurt; Lindenmaier, Werner; Alici, Evren; Graça, Luís; Cruz, Pedro Estilita; Cruz, Helder Joaquim; Bárcia, Rita Nogueira

    2014-01-17

    Standardization of mesenchymal stromal cells (MSCs) manufacturing is urgently needed to enable translational activities and ultimately facilitate comparison of clinical trial results. In this work we describe the adaptation of a proprietary method for isolation of a specific umbilical cord tissue-derived population of MSCs, herein designated by its registered trademark as UCX®, towards the production of an advanced therapy medicinal product (ATMP). The adaptation focused on different stages of production, from cell isolation steps to cell culturing and cryopreservation. The origin and quality of materials and reagents were considered and steps for avoiding microbiological and endotoxin contamination of the final cell product were implemented. Cell isolation efficiency, MSCs surface markers and genetic profiles, originating from the use of different medium supplements, were compared. The ATMP-compliant UCX® product was also cryopreserved avoiding the use of dimethyl sulfoxide, an added benefit for the use of these cells as an ATMP. Cells were analyzed for expansion capacity and longevity. The final cell product was further characterized by flow cytometry, differentiation potential, and tested for contaminants at various passages. Finally, genetic stability and immune properties were also analyzed. The isolation efficiency of UCX® was not affected by the introduction of clinical grade enzymes. Furthermore, isolation efficiencies and phenotype analyses revealed advantages in the use of human serum in cell culture as opposed to human platelet lysate. Initial decontamination of the tissue followed by the use of mycoplasma- and endotoxin-free materials and reagents in cell isolation and subsequent culture, enabled the removal of antibiotics during cell expansion. UCX®-ATMP maintained a significant expansion potential of 2.5 population doublings per week up to passage 15 (P15). They were also efficiently cryopreserved in a DMSO-free cryoprotectant medium with

  1. Gene Therapy With Regulatory T Cells: A Beneficial Alliance

    Directory of Open Access Journals (Sweden)

    Moanaro Biswas

    2018-03-01

    Full Text Available Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs are critical for tolerance induction to the transgene product and in some cases the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product and concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve a sustained transgene expression. Furthermore, techniques to engineer antigen-specific Treg cell populations, either through reprogramming conventional CD4+ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in preclinical studies. Thus, based upon these observations and the successful use of chimeric (IgG-based antigen receptors (CARs in antigen-specific effector T cells, different types of CAR-Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article.

  2. Progress and challenges in the development of a cell-based therapy for hemophilia A.

    Science.gov (United States)

    Fomin, M E; Togarrati, P P; Muench, M O

    2014-12-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review, we discuss the possibilities, progress, and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific induced pluripotent stem cells. © 2014 International Society on Thrombosis and Haemostasis.

  3. Bone marrow-derived cells for cardiovascular cell therapy: an optimized GMP method based on low-density gradient improves cell purity and function.

    Science.gov (United States)

    Radrizzani, Marina; Lo Cicero, Viviana; Soncin, Sabrina; Bolis, Sara; Sürder, Daniel; Torre, Tiziano; Siclari, Francesco; Moccetti, Tiziano; Vassalli, Giuseppe; Turchetto, Lucia

    2014-09-27

    Cardiovascular cell therapy represents a promising field, with several approaches currently being tested. The advanced therapy medicinal product (ATMP) for the ongoing METHOD clinical study ("Bone marrow derived cell therapy in the stable phase of chronic ischemic heart disease") consists of fresh mononuclear cells (MNC) isolated from autologous bone marrow (BM) through density gradient centrifugation on standard Ficoll-Paque. Cells are tested for safety (sterility, endotoxin), identity/potency (cell count, CD45/CD34/CD133, viability) and purity (contaminant granulocytes and platelets). BM-MNC were isolated by density gradient centrifugation on Ficoll-Paque. The following process parameters were optimized throughout the study: gradient medium density; gradient centrifugation speed and duration; washing conditions. A new manufacturing method was set up, based on gradient centrifugation on low density Ficoll-Paque, followed by 2 washing steps, of which the second one at low speed. It led to significantly higher removal of contaminant granulocytes and platelets, improving product purity; the frequencies of CD34+ cells, CD133+ cells and functional hematopoietic and mesenchymal precursors were significantly increased. The methodological optimization described here resulted in a significant improvement of ATMP quality, a crucial issue to clinical applications in cardiovascular cell therapy.

  4. [Gene therapy and cell transplantation for Parkinson's disease].

    Science.gov (United States)

    Muramatsu, Shin-ichi

    2005-11-01

    Increasing enthusiasm in the field of stem cell research is raising the hope of novel cell replacement therapies for Parkinson's disease (PD), but it also raises both scientific and ethical concerns. In most cases, dopaminergic cells are transplanted ectopically into the striatum instead of the substantia nigra. If the main mechanism underlying any observed functional recovery with these cell replacement therapies is restoration of dopaminergic neurotransmission, then viral vector-mediated gene delivery of dopamine-synthesizing enzymes is a more straight forward approach. The development of a recombinant adeno-associated viral (AAV) vector is making gene therapy for PD a feasible therapeutic option in the clinical arena. Efficient and long-term expression of genes for dopamine-synthesizing enzymes in the striatum restored local dopamine production and allowed behavioral recovery in animal models of PD. A clinical trial to evaluate the safety and efficacy of AAV vector-mediated gene transfer of aromatic L-amino acid decarboxylase, an enzyme that converts L-dopa to dopamine, is underway. With this strategy patients would still need to take L-dopa to control their PD symptoms, however, dopamine production could be regulated by altering the dose of L-dopa. Another AAV vector-based clinical trial is also ongoing in which the subthalamic nucleus is transduced to produce inhibitory transmitters.

  5. Progress and challenges in the development of a cell-based therapy for hemophilia A

    Science.gov (United States)

    Fomin, Marina E.; Togarrati, Padma Priya; Muench, Marcus O.

    2015-01-01

    Hemophilia A results from an insufficiency of factor VIII (FVIII). Although replacement therapy with plasma-derived or recombinant FVIII is a life-saving therapy for hemophilia A patients, such therapy is a life-long treatment rather than a cure for the disease. In this review we discuss the possibilities, progress and challenges that remain in the development of a cell-based cure for hemophilia A. The success of cell therapy depends on the type and availability of donor cells, the age of the host and method of transplantation, and the levels of engraftment and production of FVIII by the graft. Early therapy, possibly even prenatal transplantation, may yield the highest levels of engraftment by avoiding immunological rejection of the graft. Potential cell sources of FVIII include a specialized subset of endothelial cells known as liver sinusoidal endothelial cells (LSECs) present in the adult and fetal liver, or patient-specific endothelial cells derived from induced pluripotent stem cells (iPSCs) that have undergone gene editing to produce FVIII. Achieving sufficient engraftment of transplanted LSECs is one of the obstacles to successful cell therapy for hemophilia A. We discuss recent results from transplants performed in animals that show production of functional and clinically relevant levels of FVIII obtained from donor LSECs. Hence, the possibility of treating hemophilia A can be envisioned through persistent production of FVIII from transplanted donor cells derived from a number of potential cell sources or through creation of donor endothelial cells from patient-specific iPSCs. PMID:25297648

  6. Clinical application of cell, gene and tissue therapies in Spain.

    Science.gov (United States)

    Gálvez-Martín, P; Ruiz, A; Clares, B

    2018-05-01

    Scientific and technical advances in the areas of biomedicine and regenerative medicine have enabled the development of new treatments known as "advanced therapies", which encompass cell therapy, genetics and tissue engineering. The biologic products that can be manufactured from these elements are classified from the standpoint of the Spanish Agency of Medication and Health Products in advanced drug therapies, blood products and transplants. This review seeks to provide scientific and administrative information for clinicians on the use of these biologic resources. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  7. The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

    Science.gov (United States)

    Trounson, Alan; DeWitt, Natalie D; Feigal, Ellen G

    2012-01-01

    Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies.

  8. Gene and cell therapy for children — New medicines, new challenges?☆

    Science.gov (United States)

    Buckland, Karen F.; Bobby Gaspar, H.

    2014-01-01

    The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances

  9. Tumorigenicity studies for human pluripotent stem cell-derived products.

    Science.gov (United States)

    Kuroda, Takuya; Yasuda, Satoshi; Sato, Yoji

    2013-01-01

    Human pluripotent stem cells (hPSCs), i.e. human embryonic stem cells and human induced pluripotent stem cells, are able to self-renew and differentiate into multiple cell types. Because of these abilities, numerous attempts have been made to utilize hPSCs in regenerative medicine/cell therapy. hPSCs are, however, also tumorigenic, that is, they can give rise to the progressive growth of tumor nodules in immunologically unresponsive animals. Therefore, assessing and managing the tumorigenicity of all final products is essential in order to prevent ectopic tissue formation, tumor development, and/or malignant transformation elicited by residual pluripotent stem cells after implantation. No detailed guideline for the tumorigenicity testing of hPSC-derived products has yet been issued for regenerative medicine/cell therapy, despite the urgent necessity. Here, we describe the current situations and issues related to the tumorigenicity testing of hPSC-derived products and we review the advantages and disadvantages of several types of tumorigenicity-associated tests. We also refer to important considerations in the execution and design of specific studies to monitor the tumorigenicity of hPSC-derived products.

  10. A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies.

    Science.gov (United States)

    Lu, Tangying Lily; Pugach, Omar; Somerville, Robert; Rosenberg, Steven A; Kochenderfer, James N; Better, Marc; Feldman, Steven A

    2016-12-01

    The treatment of B-cell malignancies by adoptive cell transfer (ACT) of anti-CD19 chimeric antigen receptor T cells (CD19 CAR-T) has proven to be a highly successful therapeutic modality in several clinical trials. 1-6 The anti-CD19 CAR-T cell production method used to support initial trials relied on numerous manual, open process steps, human serum, and 10 days of cell culture to achieve a clinical dose. 7 This approach limited the ability to support large multicenter clinical trials, as well as scale up for commercial cell production. Therefore, studies were completed to streamline and optimize the original National Cancer Institute production process by removing human serum from the process in order to minimize the risk of viral contamination, moving process steps from an open system to functionally closed system operations in order to minimize the risk of microbial contamination, and standardizing additional process steps in order to maximize process consistency. This study reports a procedure for generating CD19 CAR-T cells in 6 days, using a functionally closed manufacturing process and defined, serum-free medium. This method is able to produce CD19 CAR-T cells that are phenotypically and functionally indistinguishable from cells produced for clinical trials by the previously described production process.

  11. Clinical manufacturing of CAR T cells: foundation of a promising therapy

    Science.gov (United States)

    Wang, Xiuyan; Rivière, Isabelle

    2016-01-01

    The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality. PMID:27347557

  12. Clinical manufacturing of CAR T cells: foundation of a promising therapy

    Directory of Open Access Journals (Sweden)

    Xiuyan Wang

    2016-01-01

    Full Text Available The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality.

  13. Bags versus flasks: a comparison of cell culture systems for the production of dendritic cell-based immunotherapies.

    Science.gov (United States)

    Fekete, Natalie; Béland, Ariane V; Campbell, Katie; Clark, Sarah L; Hoesli, Corinne A

    2018-04-19

    In recent years, cell-based therapies targeting the immune system have emerged as promising strategies for cancer treatment. This review summarizes manufacturing challenges related to production of antigen presenting cells as a patient-tailored cancer therapy. Understanding cell-material interactions is essential because in vitro cell culture manipulations to obtain mature antigen-producing cells can significantly alter their in vivo performance. Traditional antigen-producing cell culture protocols often rely on cell adhesion to surface-treated hydrophilic polystyrene flasks. More recent commercial and investigational cancer immunotherapy products were manufactured using suspension cell culture in closed hydrophobic fluoropolymer bags. The shift to closed cell culture systems can decrease risks of contamination by individual operators, as well as facilitate scale-up and automation. Selecting closed cell culture bags over traditional open culture systems entails different handling procedures and processing controls, which can affect product quality. Changes in culture vessels also entail changes in vessel materials and geometry, which may alter the cell microenvironment and resulting cell fate decisions. Strategically designed culture systems will pave the way for the generation of more sophisticated and highly potent cell-based cancer vaccines. As an increasing number of cell-based therapies enter the clinic, the selection of appropriate cell culture vessels and materials becomes a critical consideration that can impact the therapeutic efficacy of the product, and hence clinical outcomes and patient quality of life. © 2018 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

  14. Stem cells engineering for cell-based therapy.

    Science.gov (United States)

    Taupin, Philippe

    2007-09-01

    Stem cells carry the promise to cure a broad range of diseases and injuries, from diabetes, heart and muscular diseases, to neurological diseases, disorders and injuries. Significant progresses have been made in stem cell research over the past decade; the derivation of embryonic stem cells (ESCs) from human tissues, the development of cloning technology by somatic cell nuclear transfer (SCNT) and the confirmation that neurogenesis occurs in the adult mammalian brain and that neural stem cells (NSCs) reside in the adult central nervous system (CNS), including that of humans. Despite these advances, there may be decades before stem cell research will translate into therapy. Stem cell research is also subject to ethical and political debates, controversies and legislation, which slow its progress. Cell engineering has proven successful in bringing genetic research to therapy. In this review, I will review, in two examples, how investigators are applying cell engineering to stem cell biology to circumvent stem cells' ethical and political constraints and bolster stem cell research and therapy.

  15. American Society of Gene & Cell Therapy

    Science.gov (United States)

    ... Gene & Cell Therapy Defined Gene therapy and cell therapy are overlapping fields of biomedical research that aim to repair the direct cause of genetic diseases. Read More Gene & Cell Therapy FAQ's Read the most common questions raised by ...

  16. [Report from the Committee for Advanced Therapies (CAT). Pitfalls on the way from concept to medical treatment with advanced therapy medicinal products].

    Science.gov (United States)

    Reiss, M; Büttel, I C; Schneider, C K

    2011-07-01

    Advanced therapy medicinal products (ATMP) are highly innovative and complex medicines. They comprise gene therapy medicinal products, somatic cell therapy medicinal products, and tissue-engineered products (TEP). With the European Regulation on ATMP that came into force in 2008, a consolidated regulatory framework was created, where the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA) plays a central role. This article discusses pitfalls and challenges that the CAT has experienced in its discussions of various procedures. Often ATMPs are developed by small and medium-sized enterprises (SME) which also face nonscientific challenges. The CAT wishes to meet these challenges on a scientific and regulatory level during its 2010-2015 work program.

  17. Cell-based product classification procedure: What can be done differently to improve decisions on borderline products?

    Science.gov (United States)

    Izeta, Ander; Herrera, Concha; Mata, Rosario; Astori, Giuseppe; Giordano, Rosaria; Hernández, Carmen; Leyva, Laura; Arias, Salvador; Oyonarte, Salvador; Carmona, Gloria; Cuende, Natividad

    2016-07-01

    In June 2015, European Medicines Agency/Committee for Advanced Therapies (CAT) released the new version of the reflection paper on classification of advanced therapy medicinal products (ATMPs) established to address questions of borderline cases in which classification of a product based on genes, cells or tissues is unclear. The paper shows CAT's understanding of substantial manipulation and essential function(s) criteria that define the legal scope of cell-based medicinal products. This article aims to define the authors' viewpoint on the reflection paper. ATMP classification has intrinsic weaknesses derived from the lack of clarity of the evolving concepts of substantial manipulation and essential function(s) as stated in the EU Regulation, leading to the risk of differing interpretations and misclassification. This might result in the broadening of ATMP scope at the expense of other products such as cell/tissue transplants and blood products, or even putting some present and future clinical practice at risk of being classified as ATMP. Because of the major organizational, economic and regulatory implications of product classification, we advocate for increased interaction between CAT and competent authorities (CAs) for medicines, blood and blood components and tissues and cells or for the creation of working groups including representatives of all parties as recently suggested by several CAs. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  18. Combination of nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy as a novel therapeutic application to manage the pain and treat many clinical conditions

    Science.gov (United States)

    Halasa, Salaheldin; Dickinson, Eva

    2014-02-01

    From hypertension to diabetes, cancer to HIV, stroke to memory loss and learning disorders to septic shock, male impotence to tuberculosis, there is probably no pathological condition where nitric oxide does not play an important role. Nitric oxide is an analgesic, immune-modulator, vasodilator, anti-apoptotic, growth modulator, angiogenetic, anti-thrombotic, anti-inflammatory and neuro-modulator. Because of the above actions of nitric oxide, many clinical conditions associated with abnormal Nitric oxide (NO) production and bioavailability. Our novel therapeutic approach is to restore the homeostasis of nitric oxide and replace the lost cells by combining nitric oxide therapy, anti-oxidative therapy, low level laser therapy, plasma rich platelet therapy and stem cell therapy.

  19. Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease

    DEFF Research Database (Denmark)

    Fox, Ira J; Daley, George Q; Goldman, Steven A

    2014-01-01

    Pluripotent stem cells (PSCs) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically affect blood component and hematopoietic stem cell therapies and should facilitate......, and industry is critical for generating new stem cell-based therapies....... treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types is needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful...

  20. Skin Stem Cells in Skin Cell Therapy

    Directory of Open Access Journals (Sweden)

    Mollapour Sisakht

    2015-12-01

    Full Text Available Context Preclinical and clinical research has shown that stem cell therapy is a promising therapeutic option for many diseases. This article describes skin stem cells sources and their therapeutic applications. Evidence Acquisition Compared with conventional methods, cell therapy reduces the surgical burden for patients because it is simple and less time-consuming. Skin cell therapy has been developed for variety of diseases. By isolation of the skin stem cell from the niche, in vitro expansion and transplantation of cells offers a surprising healing capacity profile. Results Stem cells located in skin cells have shown interesting properties such as plasticity, transdifferentiation, and specificity. Mesenchymal cells of the dermis, hypodermis, and other sources are currently being investigated to promote regeneration. Conclusions Because skin stem cells are highly accessible from autologous sources and their immunological profile is unique, they are ideal for therapeutic approaches. Optimization of administrative routes requires more investigation own to the lack of a standard protocol.

  1. nduced pluripotent stem cells and cell therapy

    Directory of Open Access Journals (Sweden)

    Banu İskender

    2013-12-01

    Full Text Available Human embryonic stem cells are derived from the inner cell mass of a blastocyst-stage embryo. They hold a huge promise for cell therapy with their self-renewing ability and pluripotency, which is known as the potential to differentiate into all cell types originating from three embryonic germ layers. However, their unique pluripotent feature could not be utilised for therapeutic purposes due to the ethical and legal problems during derivation. Recently, it was shown that the cells from adult tissues could be reverted into embryonic state, thereby restoring their pluripotent feature. This has strenghtened the possiblity of directed differentition of the reprogrammed somatic cells into the desired cell types in vitro and their use in regenerative medicine. Although these cells were termed as induced pluripotent cells, the mechanism of pluripotency has yet to be understood. Still, induced pluripotent stem cell technology is considered to be significant by proposing novel approaches in disease modelling, drug screening and cell therapy. Besides their self-renewing ability and their potential to differentiate into all cell types in a human body, they arouse a great interest in scientific world by being far from the ethical concerns regarding their embryonic counterparts and their unique feature of being patient-specific in prospective cell therapies. In this review, induced pluripotent stem cell technology and its role in cell-based therapies from past to present will be discussed. J Clin Exp Invest 2013; 4 (4: 550-561

  2. Stem cell therapy for diabetes

    Directory of Open Access Journals (Sweden)

    K O Lee

    2012-01-01

    Full Text Available Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

  3. A quality risk management model approach for cell therapy manufacturing.

    Science.gov (United States)

    Lopez, Fabio; Di Bartolo, Chiara; Piazza, Tommaso; Passannanti, Antonino; Gerlach, Jörg C; Gridelli, Bruno; Triolo, Fabio

    2010-12-01

    International regulatory authorities view risk management as an essential production need for the development of innovative, somatic cell-based therapies in regenerative medicine. The available risk management guidelines, however, provide little guidance on specific risk analysis approaches and procedures applicable in clinical cell therapy manufacturing. This raises a number of problems. Cell manufacturing is a poorly automated process, prone to operator-introduced variations, and affected by heterogeneity of the processed organs/tissues and lot-dependent variability of reagent (e.g., collagenase) efficiency. In this study, the principal challenges faced in a cell-based product manufacturing context (i.e., high dependence on human intervention and absence of reference standards for acceptable risk levels) are identified and addressed, and a risk management model approach applicable to manufacturing of cells for clinical use is described for the first time. The use of the heuristic and pseudo-quantitative failure mode and effect analysis/failure mode and critical effect analysis risk analysis technique associated with direct estimation of severity, occurrence, and detection is, in this specific context, as effective as, but more efficient than, the analytic hierarchy process. Moreover, a severity/occurrence matrix and Pareto analysis can be successfully adopted to identify priority failure modes on which to act to mitigate risks. The application of this approach to clinical cell therapy manufacturing in regenerative medicine is also discussed. © 2010 Society for Risk Analysis.

  4. Gene and Cell Therapy for β-Thalassemia and Sickle Cell Disease with Induced Pluripotent Stem Cells (iPSCs): The Next Frontier.

    Science.gov (United States)

    Papapetrou, Eirini P

    2017-01-01

    In recent years, breakthroughs in human pluripotent stem cell (hPSC) research, namely cellular reprogramming and the emergence of sophisticated genetic engineering technologies, have opened new frontiers for cell and gene therapy. The prospect of using hPSCs, either autologous or histocompatible, as targets of genetic modification and their differentiated progeny as cell products for transplantation, presents a new paradigm of regenerative medicine of potential tremendous value for the treatment of blood disorders, including beta-thalassemia (BT) and sickle cell disease (SCD). Despite advances at a remarkable pace and great promise, many roadblocks remain before clinical translation can be realistically considered. Here we discuss the theoretical advantages of cell therapies utilizing hPSC derivatives, recent proof-of-principle studies and the main challenges towards realizing the potential of hPSC therapies in the clinic.

  5. Cell Therapy in Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Hoda Madani

    2014-05-01

    Full Text Available   Recently, cell therapy has sparked a revolution in ischemic heart disease that will in the future help clinicians to cure patients. Earlier investigations in animal models and clinical trials have suggested that positive paracrine effects such as neoangiogenesis and anti-apoptotic can improve myocardial function. In this regard the Royan cell therapy center designed a few trials in collaboration with multi hospitals such as Baqiyatallah, Shahid Lavasani, Tehran Heart Center, Shahid rajaee, Masih daneshvari, Imam Reza, Razavi and Sasan from 2006. Their results were interesting. However, cardiac stem cell therapy still faces great challenges in optimizing the treatment of patients. Keyword: Cardiovascular disease, Cell therapy.  

  6. Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

    Science.gov (United States)

    Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

    2011-01-01

    Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID:21540837

  7. Current advanced therapy cell-based medicinal products for type-1-diabetes treatment.

    Science.gov (United States)

    Cañibano-Hernández, Alberto; Del Burgo, Laura Sáenz; Espona-Noguera, Albert; Ciriza, Jesús; Pedraz, Jose Luis

    2018-03-27

    In the XXI century diabetes mellitus has become one of the main threats to human health with higher incidence in regions such as Europe and North America. Type 1 diabetes mellitus (T1DM) occurs as a consequence of the immune-mediated destruction of insulin producing β-cells located in the endocrine part of the pancreas, the islets of Langerhans. The administration of exogenous insulin through daily injections is the most prominent treatment for T1DM but its administration is frequently associated to failure in glucose metabolism control, finally leading to hyperglycemia episodes. Other approaches have been developed in the past decades, such as whole pancreas and islet allotransplantation, but they are restricted to patients who exhibit frequent episodes of hypoglycemia or renal failure because the lack of donors and islet survival. Moreover, patients transplanted with either whole pancreas or islets require of immune suppression to avoid the rejection of the transplant. Currently, advanced therapy medicinal products (ATMP), such as implantable devices, have been developed in order to reduce immune rejection response while increasing cell survival. To overcome these issues, ATMPs must promote vascularization, guaranteeing the nutritional contribution, while providing O 2 until vasculature can surround the device. Moreover, it should help in the immune-protection to avoid acute and chronic rejection. The transplanted cells or islets should be embedded within biomaterials with tunable properties like injectability, stiffness and porosity mimicking natural ECM structural characteristics. And finally, an infinitive cell source that solves the donor scarcity should be found such as insulin producing cells derived from mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Several companies have registered their ATMPs and future studies envision new prototypes. In this review, we will discuss the mechanisms and etiology of

  8. Pigment Production Analysis in Human Melanoma Cells.

    Science.gov (United States)

    Hopkin, Amelia Soto; Paterson, Elyse K; Ruiz, Rolando; Ganesan, Anand K

    2016-05-25

    The human epidermal melanocyte is a highly specialized pigmented cell that serves to protect the epidermis from ultraviolet (UV) damage through the production of melanin, or melanogenesis. Misregulation in melanogenesis leading to either hyper- or hypo-pigmentation is found in human diseases such as malasma and vitiligo. Current therapies for these diseases are largely unsuccessful and the need for new therapies is necessary. In order to identify genes and or compounds that can alter melanogenesis, methods are required that can detect changes in pigment production as well as expression of key melanogenesis transcription factors and enzymes. Here we describe methods to detect changes in melanogenesis in a human melanoma cell line, MNT-1, by (1) analyzing pigment production by measuring the absorbance of melanin present by spectrophotometry, (2) analyzing transcript expression of potent regulators of melanogenesis by qunatitative reverse-transcription (RT)PCR and (3) analyzing protein expression of potent regulators of melanogenesis by Western blot (WB).

  9. The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products.

    Science.gov (United States)

    Rafiq, Qasim A; Ortega, Ilida; Jenkins, Stuart I; Wilson, Samantha L; Patel, Asha K; Barnes, Amanda L; Adams, Christopher F; Delcassian, Derfogail; Smith, David

    2015-11-01

    Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.

  10. Single agent- and combination treatment with two targeted suicide gene therapy systems is effective in chemoresistant small cell lung cancer cells

    DEFF Research Database (Denmark)

    Michaelsen, Signe R; Christensen, Camilla L; Sehested, Maxwell

    2012-01-01

    Transcriptional targeted suicide gene (SG) therapy driven by the insulinoma-associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to small cell lung cancer (SCLC) cells and tumors. It remains to be determined whether acquired chemoresistance......, as observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter-driven SG therapy....

  11. Cancer stem cells and differentiation therapy.

    Science.gov (United States)

    Jin, Xiong; Jin, Xun; Kim, Hyunggee

    2017-10-01

    Cancer stem cells can generate tumors from only a small number of cells, whereas differentiated cancer cells cannot. The prominent feature of cancer stem cells is its ability to self-renew and differentiate into multiple types of cancer cells. Cancer stem cells have several distinct tumorigenic abilities, including stem cell signal transduction, tumorigenicity, metastasis, and resistance to anticancer drugs, which are regulated by genetic or epigenetic changes. Like normal adult stem cells involved in various developmental processes and tissue homeostasis, cancer stem cells maintain their self-renewal capacity by activating multiple stem cell signaling pathways and inhibiting differentiation signaling pathways during cancer initiation and progression. Recently, many studies have focused on targeting cancer stem cells to eradicate malignancies by regulating stem cell signaling pathways, and products of some of these strategies are in preclinical and clinical trials. In this review, we describe the crucial features of cancer stem cells related to tumor relapse and drug resistance, as well as the new therapeutic strategy to target cancer stem cells named "differentiation therapy."

  12. Gene Therapy of T Helper Cells in HIV Infection. Mathematical Model of the Criteria for Clinical Effect

    DEFF Research Database (Denmark)

    Lund, Ole; Lund, Ole søgaard; Gram, Gregers

    1997-01-01

    The paper presents a mathematical model of the criteria for gene therapy of T helper cells to have a clinical effect on HIV infection. Our main results are that the therapy should be designed to give the transduced cells a significant but not necessarily total protection against HIV-induced cell...... deaths, and to avoid the production of viral mutants that are insensitive to gene therapy. The transduced cells will not survive if the gene therapy only blocks the spread of virus....

  13. Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases.

    Science.gov (United States)

    Bueren, Juan A; Guenechea, Guillermo; Casado, José A; Lamana, María Luisa; Segovia, José C

    2003-01-01

    Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous stem cells. On the other hand, severe side effects in a few patients treated with gene therapy have also been reported, indicating the usefulness of further improving the vectors currently used in gene therapy clinical trials. In the field of stem cell biology, evidence showing the plastic potential of adult hematopoietic stem cells and data indicating the multipotency of adult mesenchymal precursor cells have been presented. Also, the generation of embryonic stem cells by means of nuclear transfer techniques has appeared as a new methodology with direct implications in gene therapy.

  14. Methods and practices to diversify cell-based products.

    Science.gov (United States)

    Vertès, Alain A

    2017-12-15

    Medicinal signaling cell (MSC)-based products represent emerging treatments in various therapeutic areas including cardiometabolic, inflammation, autoimmunity, orthopedics, wound healing and oncology. Exploring innovation beyond minimally manipulated plastic-adherent ex vivo expanded allogeneic MSCs enables product delineation. Product delineation is on the critical path to maximize clinical benefits and market access. An innovation framework is presented here along various innovation dimensions comprising composition-of-matter by means of positive cell surface markers, formulation varying for example the cell dose or the preservation mode and medium, manufacturing to adapt the secretome of MSCs to the condition of interest, the mode of delivery and corresponding delivery devices, as well as molecular engineering and biomarkers. The rationale of the innovation space thus described applies generally to all cell-based therapies.

  15. Temporal Progression of Retinal Progenitor Cell Identity: Implications in Cell Replacement Therapies

    Directory of Open Access Journals (Sweden)

    Awais Javed

    2017-12-01

    Full Text Available Retinal degenerative diseases, which lead to the death of rod and cone photoreceptor cells, are the leading cause of inherited vision loss worldwide. Induced pluripotent or embryonic stem cells (iPSCs/ESCs have been proposed as a possible source of new photoreceptors to restore vision in these conditions. The proof of concept studies carried out in mouse models of retinal degeneration over the past decade have highlighted several limitations for cell replacement in the retina, such as the low efficiency of cone photoreceptor production from stem cell cultures and the poor integration of grafted cells in the host retina. Current protocols to generate photoreceptors from stem cells are largely based on the use of extracellular factors. Although these factors are essential to induce the retinal progenitor cell (RPC fate from iPSCs/ESCs, developmental studies have shown that RPCs alter fate output as a function of time (i.e., their temporal identity to generate the seven major classes of retinal cell types, rather than spatial position. Surprisingly, current stem cell differentiation protocols largely ignore the intrinsic temporal identity of dividing RPCs, which we argue likely explains the low efficiency of cone production in such cultures. In this article, we briefly review the mechanisms regulating temporal identity in RPCs and discuss how they could be exploited to improve cone photoreceptor production for cell replacement therapies.

  16. Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy.

    Science.gov (United States)

    Aguila, Julio C; Hedlund, Eva; Sanchez-Pernaute, Rosario

    2012-01-01

    Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be applied in vitro to induce, select, and reprogram cells to the mesostriatal dopamine fate.

  17. TOPICAL REVIEW: Stem cells engineering for cell-based therapy

    Science.gov (United States)

    Taupin, Philippe

    2007-09-01

    Stem cells carry the promise to cure a broad range of diseases and injuries, from diabetes, heart and muscular diseases, to neurological diseases, disorders and injuries. Significant progresses have been made in stem cell research over the past decade; the derivation of embryonic stem cells (ESCs) from human tissues, the development of cloning technology by somatic cell nuclear transfer (SCNT) and the confirmation that neurogenesis occurs in the adult mammalian brain and that neural stem cells (NSCs) reside in the adult central nervous system (CNS), including that of humans. Despite these advances, there may be decades before stem cell research will translate into therapy. Stem cell research is also subject to ethical and political debates, controversies and legislation, which slow its progress. Cell engineering has proven successful in bringing genetic research to therapy. In this review, I will review, in two examples, how investigators are applying cell engineering to stem cell biology to circumvent stem cells' ethical and political constraints and bolster stem cell research and therapy.

  18. Photodynamic therapy for basal cell carcinoma.

    Science.gov (United States)

    Fargnoli, Maria Concetta; Peris, Ketty

    2015-11-01

    Topical photodynamic therapy is an effective and safe noninvasive treatment for low-risk basal cell carcinoma, with the advantage of an excellent cosmetic outcome. Efficacy of photodynamic therapy in basal cell carcinoma is supported by substantial research and clinical trials. In this article, we review the procedure, indications and clinical evidences for the use of photodynamic therapy in the treatment of basal cell carcinoma.

  19. Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Yin, Qingsong; Sivina, Mariela; Robins, Harlan; Yusko, Erik; Vignali, Marissa; O'Brien, Susan; Keating, Michael J; Ferrajoli, Alessandra; Estrov, Zeev; Jain, Nitin; Wierda, William G; Burger, Jan A

    2017-02-15

    The Bruton's tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4 + and CD8 + T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell-related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution. Copyright © 2017 by The American Association of Immunologists, Inc.

  20. Regulation of advanced therapy medicinal products in Europe and the role of academia.

    Science.gov (United States)

    Pearce, Kim F; Hildebrandt, Martin; Greinix, Hildegard; Scheding, Stefan; Koehl, Ulrike; Worel, Nina; Apperley, Jane; Edinger, Matthius; Hauser, Andrea; Mischak-Weissinger, Eva; Dickinson, Anne M; Lowdell, Mark W

    2014-03-01

    Advanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients. Academic good manufacturing practice (GMP) centers are major contributors in the development of ATMPs and this study assessed the impact of regulations on them. European academic and non-industrial facilities (n = 747) were contacted, and a representative sample of 50 replied to a detailed questionnaire. Experienced centres were further selected in every Member State (MS) for semi-structured interviews. Indicators of ATMP production and development success were statistically assessed, and opinions about directive implementation were documented. Facilities experienced in manufacturing cell therapy transplant products are the most successful in developing ATMPs. New centres lacking this background struggle to enter the field, and there remains a shortage of facilities in academia participating in translational research. This is compounded by heterogeneous implementation of the regulations across MS. GMP facilities successfully developing ATMPs are present in all MS. However, the implementation of regulations is heterogeneous between MS, with substantial differences in the definition of ATMPs and in the approved manufacturing environment. The cost of GMP compliance is underestimated by research funding bodies. This is detrimental to development of new ATMPs and commercialization of any that are successful in early clinical trials. Academic GMP practitioners should strengthen their political visibility and contribute to the development of functional and effective European Union legislation in this field. Copyright © 2014 International Society for Cellular Therapy. All rights reserved.

  1. CD34-positive cells as stem cell support after high dose therapy

    International Nuclear Information System (INIS)

    Kvalheim, G.; Pharo, A.; Holte, H.

    1996-01-01

    Six patients, five with breast cancer and one with non-Hodgkin's lymphoma, were mobilized by chemotherapy and G-CSF. CD34-positive cells were isolated by means of immunomagnetic beads and Isolex 300 Cell Separator. Mean purity of isolated CD34-positive cells was 97% and mean yield was 54%. Three patients were treated with high dose therapy followed by reinfusion of CD34-positive cells as stem cell support. Recovery of neutrophils occurred at day 8, 11 and 13 and of platelets at day 9, 14 and 32. It is concluded that immunomagnetic isolated CD34-positive cells give high purity and yield. Although use of CD34-positive cells reduces the content of contaminating tumours cells in the graft, breast cancer cells were still detectable in two out of five CD34-positive cell products. 20 refs., 2 figs., 1 tab

  2. Regulatory requirements for clinical trial and marketing authorisation application for cell-based medicinal products.

    Science.gov (United States)

    Salmikangas, P; Flory, E; Reinhardt, J; Hinz, T; Maciulaitis, R

    2010-01-01

    The new era of regenerative medicine has led to rapid development of new innovative therapies especially for diseases and tissue/organ defects for which traditional therapies and medicinal products have not provided satisfactory outcome. Although the clinical use and developments of cell-based medicinal products (CBMPs) could be witnessed already for a decade, robust scientific and regulatory provisions for these products have only recently been enacted. The new Regulation for Advanced Therapies (EC) 1394/2007 together with the revised Annex I, Part IV of Directive 2001/83/EC provides the new legal framework for CBMPs. The wide variety of cell-based products and the foreseen limitations (small sample sizes, short shelf life) vs. particular risks (microbiological purity, variability, immunogenicity, tumourigenicity) associated with CBMPs have called for a flexible, case-by-case regulatory approach for these products. Consequently, a risk-based approach has been developed to allow definition of the amount of scientific data needed for a Marketing Authorisation Application (MAA) of each CBMP. The article provides further insight into the initial risk evaluation, as well as to the quality, non-clinical, and clinical requirements of CBMPs. Special somatic cell therapies designed for active immunotherapy are also addressed.

  3. Stem cell therapy for ischemic heart diseases.

    Science.gov (United States)

    Yu, Hong; Lu, Kai; Zhu, Jinyun; Wang, Jian'an

    2017-01-01

    Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. Key recent published literatures and ClinicalTrials.gov. Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  4. [Ethical aspects of human embryonic stem cell use and commercial umbilical cord blood stem cell banking. Ethical reflections on the occasion of the regulation of the European Council and Parliament on advanced therapy medicinal products].

    Science.gov (United States)

    Virt, G

    2010-01-01

    The regulation of the European Council and Parliament on advanced therapy medicinal products also includes therapies with human embryonic stem cells. The use of these stem cells is controversially and heavily discussed. Contrary to the use of adult stem cells, medical and ethical problems concerning the use of human embryonic stem cells persists, because this use is based on the destruction of human life at the very beginning. The regulation foresees, therefore, subsidiarity within the European Member States. Although there are no ethical problems in principle with the use of stem cells from the umbilical cord blood, there are social ethical doubts with the banking of these stem cells for autologous use without any currently foreseeable medical advantage by commercial blood banks. Also in this case subsidiarity is valid.

  5. Alternative Cell Sources to Adult Hepatocytes for Hepatic Cell Therapy.

    Science.gov (United States)

    Pareja, Eugenia; Gómez-Lechón, María José; Tolosa, Laia

    2017-01-01

    Adult hepatocyte transplantation is limited by scarce availability of suitable donor liver tissue for hepatocyte isolation. New cell-based therapies are being developed to supplement whole-organ liver transplantation, to reduce the waiting-list mortality rate, and to obtain more sustained and significant metabolic correction. Fetal livers and unsuitable neonatal livers for organ transplantation have been proposed as potential useful sources of hepatic cells for cell therapy. However, the major challenge is to use alternative cell sources for transplantation that can be derived from reproducible methods. Different types of stem cells with hepatic differentiation potential are eligible for generating large numbers of functional hepatocytes for liver cell therapy to treat degenerative disorders, inborn hepatic metabolic diseases, and organ failure. Clinical trials are designed to fully establish the safety profile of such therapies and to define target patient groups and standardized protocols.

  6. Stem cell therapies in preclinical models of stroke. Is the aged brain microenvironment refractory to cell therapy?

    Science.gov (United States)

    Sandu, Raluca Elena; Balseanu, Adrian Tudor; Bogdan, Catalin; Slevin, Mark; Petcu, Eugen; Popa-Wagner, Aurel

    2017-08-01

    Stroke is a devastating disease demanding vigorous search for new therapies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments that may be related to unfavorable age-associated environments. Recent results using a variety of drug, cell therapy or combination thereof suggest that, (i) treatment with Granulocyte-Colony Stimulating Factor (G-CSF) in aged rats has primarily a beneficial effect on functional outcome most likely via supportive cellular processes such as neurogenesis; (ii) the combination therapy, G-CSF with mesenchymal cells (G-CSF+BM-MSC or G-CSF+BM-MNC) did not further improve behavioral indices, neurogenesis or infarct volume as compared to G-CSF alone in aged animals; (iii) better results with regard to integration of transplanted cells in the aged rat environment have been obtained using iPS of human origin; (iv) mesenchymal cells may be used as drug carriers for the aged post-stroke brains. While the middle aged brain does not seem to impair drug and cell therapies, in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time. Copyright © 2017. Published by Elsevier Inc.

  7. Cell therapy-processing economics: small-scale microfactories as a stepping stone toward large-scale macrofactories.

    Science.gov (United States)

    Harrison, Richard P; Medcalf, Nicholas; Rafiq, Qasim A

    2018-03-01

    Manufacturing methods for cell-based therapies differ markedly from those established for noncellular pharmaceuticals and biologics. Attempts to 'shoehorn' these into existing frameworks have yielded poor outcomes. Some excellent clinical results have been realized, yet emergence of a 'blockbuster' cell-based therapy has so far proved elusive.  The pressure to provide these innovative therapies, even at a smaller scale, remains. In this process, economics research paper, we utilize cell expansion research data combined with operational cost modeling in a case study to demonstrate the alternative ways in which a novel mesenchymal stem cell-based therapy could be provided at small scale. This research outlines the feasibility of cell microfactories but highlighted that there is a strong pressure to automate processes and split the quality control cost-burden over larger production batches. The study explores one potential paradigm of cell-based therapy provisioning as a potential exemplar on which to base manufacturing strategy.

  8. Regulating the advertising and promotion of stem cell therapies.

    Science.gov (United States)

    von Tigerstrom, Barbara

    2017-10-01

    There are widespread concerns with the ways in which 'unproven' stem cell therapies are advertised to patients. This article explores the potential and limits of using laws that regulate advertising and promotion as a tool to address these concerns. It examines general consumer protection laws and laws and policies on advertising medical products and services, focusing on the USA, Canada and Australia. The content of existing laws and policies covers most of the marketing practices that cause concern, but several systemic factors are likely to limit enforcement efforts. Potential reforms in Australia that would prevent direct-to-consumer advertising of autologous cell therapies are justified in principle and should be considered by other jurisdictions, but again face important practical limits to their effectiveness.

  9. Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)

    Science.gov (United States)

    Huang, Hongyun; Young, Wise; Chen, Lin; Feng, Shiqing; Zoubi, Ziad M. Al; Sharma, Hari Shanker; Saberi, Hooshang; Moviglia, Gustavo A.; He, Xijing; Muresanu, Dafin F.; Sharma, Alok; Otom, Ali; Andrews, Russell J.; Al-Zoubi, Adeeb; Bryukhovetskiy, Andrey S.; Chernykh, Elena R.; Domańska-Janik, Krystyna; Jafar, Emad; Johnson, W. Eustace; Li, Ying; Li, Daqing; Luan, Zuo; Mao, Gengsheng; Shetty, Ashok K.; Siniscalco, Dario; Skaper, Stephen; Sun, Tiansheng; Wang, Yunliang; Wiklund, Lars; Xue, Qun; You, Si-Wei; Zheng, Zuncheng; Dimitrijevic, Milan R.; Masri, W. S. El; Sanberg, Paul R.; Xu, Qunyuan; Luan, Guoming; Chopp, Michael; Cho, Kyoung-Suok; Zhou, Xin-Fu; Wu, Ping; Liu, Kai; Mobasheri, Hamid; Ohtori, Seiji; Tanaka, Hiroyuki; Han, Fabin; Feng, Yaping; Zhang, Shaocheng; Lu, Yingjie; Zhang, Zhicheng; Rao, Yaojian; Tang, Zhouping; Xi, Haitao; Wu, Liang; Shen, Shunji; Xue, Mengzhou; Xiang, Guanghong; Guo, Xiaoling; Yang, Xiaofeng; Hao, Yujun; Hu, Yong; Li, Jinfeng; AO, Qiang; Wang, Bin; Zhang, Zhiwen; Lu, Ming; Li, Tong

    2018-01-01

    Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version “Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)”. The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility. PMID:29637817

  10. Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy.

    Science.gov (United States)

    Tang, Xiang-Jun; Sun, Xu-Yong; Huang, Kuan-Ming; Zhang, Li; Yang, Zhuo-Shun; Zou, Dan-Dan; Wang, Bin; Warnock, Garth L; Dai, Long-Jun; Luo, Jie

    2015-12-29

    Chimeric antigen receptor (CAR)-based T-cell adoptive immunotherapy is a distinctively promising therapy for cancer. The engineering of CARs into T cells provides T cells with tumor-targeting capabilities and intensifies their cytotoxic activity through stimulated cell expansion and enhanced cytokine production. As a novel and potent therapeutic modality, there exists some uncontrollable processes which are the potential sources of adverse events. As an extension of this impactful modality, CAR-T cell-derived exosomes may substitute CAR-T cells to act as ultimate attackers, thereby overcoming some limitations. Exosomes retain most characteristics of parent cells and play an essential role in intercellular communications via transmitting their cargo to recipient cells. The application of CAR-T cell-derived exosomes will make this cell-based therapy more clinically controllable as it also provides a cell-free platform to diversify anticancer mediators, which responds effectively to the complexity and volatility of cancer. It is believed that the appropriate application of both cellular and exosomal platforms will make this effective treatment more practicable.

  11. Advanced Therapy Medicinal Products in type I diabetes mellitus: technological and regulatory challenges

    Directory of Open Access Journals (Sweden)

    Camila Leal-Lopes

    2018-02-01

    Full Text Available Introduction: Type 1 Diabetes mellitus (T1DM is an autoimmune disorder which arises from the destruction of insulin-producing pancreatic β-cells. Currently, Brazil’s advanced therapy medicinal products (ATMP, developed for clinical research and therapeutic purposes, take place in the so-called Cellular Technology Centers (CTC, according to the Resolution nº. 9/2011 of the Collegiate Board of Directors (RDC, enacted by the National Health Surveillance Agency (Anvisa. Objective: This study was conducted with the main objective of describing and discussing the development of ATMP for T1DM treatment. Method: A qualitative research, narrative review and critical discussion of the literature were under taken. Results: ATMP promote new therapeutic approaches for Diabetes, holding great potential to restore the patients’ endogenous insulin secretion, improving their life quality, overcoming the chronic complications of Diabetes and reducing the socioeconomic burden. Nowadays, ATMP in T1DM comprise: a cell therapy; b gene therapy products; c tissue engineering and d ATMPassociated to biopharmaceutical products. Conclusions: Further research should contribute to stimulate public and private organizations to effectively act towards reducing the impact of Diabetes on individuals and the society as a whole. It is essential that Brazilian legislation closely follows the biotechnological developments, supporting the scientific progress and benefiting T1DM patients with modern and cutting-edge therapies.

  12. Stem-cell-derived products: an FDA update.

    Science.gov (United States)

    Moos, Malcolm

    2008-12-01

    The therapeutic potential of products derived from stem cells of various types has prompted increasing research and development and public attention. Initiation of human clinical trials in the not-too-distant future is now a realistic possibility. It is, therefore, important to weigh the potential benefits against known, theoretical and totally unsuspected risks in light of current knowledge to ensure that subjects participating in these trials are afforded the most reasonable balance possible between potential risks and potential benefits. There are no apparent differences in fundamental, qualitative biological characteristics between stem-cell-derived products and other cellular therapies regulated by the United States Food and Drug Administration (FDA). Existing authorities can, therefore, be applied. Nevertheless, these products do have properties that require careful evaluation.

  13. Cell therapy for intervertebral disc repair: advancing cell therapy from bench to clinics

    Directory of Open Access Journals (Sweden)

    LM Benneker

    2014-05-01

    Full Text Available Intervertebral disc (IVD degeneration is a major cause of pain and disability; yet therapeutic options are limited and treatment often remains unsatisfactory. In recent years, research activities have intensified in tissue engineering and regenerative medicine, and pre-clinical studies have demonstrated encouraging results. Nonetheless, the translation of new biological therapies into clinical practice faces substantial barriers. During the symposium "Where Science meets Clinics", sponsored by the AO Foundation and held in Davos, Switzerland, from September 5-7, 2013, hurdles for translation were outlined, and ways to overcome them were discussed. With respect to cell therapy for IVD repair, it is obvious that regenerative treatment is indicated at early stages of disc degeneration, before structural changes have occurred. It is envisaged that in the near future, screening techniques and non-invasive imaging methods will be available to detect early degenerative changes. The promises of cell therapy include a sustained effect on matrix synthesis, inflammation control, and prevention of angio- and neuro-genesis. Discogenic pain, originating from "black discs" or annular injury, prevention of adjacent segment disease, and prevention of post-discectomy syndrome were identified as prospective indications for cell therapy. Before such therapy can safely and effectively be introduced into clinics, the identification of the patient population and proper standardisation of diagnostic parameters and outcome measurements are indispensable. Furthermore, open questions regarding the optimal cell type and delivery method need to be resolved in order to overcome the safety concerns implied with certain procedures. Finally, appropriate large animal models and well-designed clinical studies will be required, particularly addressing safety aspects.

  14. Risk of discontinuation of Advanced Therapy Medicinal Products clinical trials.

    Science.gov (United States)

    Hanna, Eve; Rémuzat, Cecile; Auquier, Pascal; Toumi, Mondher

    2016-01-01

    Advanced therapy medicinal products (ATMPs) constitute a class of innovative products that encompasses gene therapy, somatic cell therapy, and tissue-engineered products (TEP). There is an increased investment of commercial and non-commercial sponsors in this field and a growing number of ATMPs randomized clinical trials (RCT) and patients enrolled in such trials. RCT generate data to prove the efficacy of a new therapy, but the discontinuation of RCTs wastes scarce resources. Our objective is to identify the number and characteristics of discontinued ATMPs trials in order to evaluate the rate of discontinuation. We searched for ATMPs trials conducted between 1999 to June 2015 using three databases, which are Clinicaltrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the EU Drug Regulating Authorities Clinical Trials (EudraCT). We selected the ATMPs trials after elimination of the duplicates. We identified the disease areas and the sponsors as commercial or non-commercial organizations. We classified ATMPs by type and trial status, that is, ongoing, completed, terminated, discontinued, and prematurely ended. Then, we calculated the rate of discontinuation. Between 1999 and June 2015, 143 withdrawn, terminated, or prematurely ended ATMPs clinical trials were identified. Between 1999 and June 2013, 474 ongoing and completed clinical trials were identified. Therefore, the rate of discontinuation of ATMPs trials is 23.18%, similar to that for non-ATMPs drugs in development. The probability of discontinuation is, respectively, 27.35, 16.28, and 16.34% for cell therapies, gene therapies, and TEP. The highest discontinuation rate is for oncology (43%), followed by cardiology (19.2%). It is almost the same for commercial and non-commercial sponsors; therefore, the discontinuation reason may not be financially driven. No failure risk rate per development phase is available for ATMPs. The discontinuation rate may prove helpful when assessing the

  15. Combination cell therapy with mesenchymal stem cells and neural stem cells for brain stroke in rats.

    Science.gov (United States)

    Hosseini, Seyed Mojtaba; Farahmandnia, Mohammad; Razi, Zahra; Delavari, Somayeh; Shakibajahromi, Benafsheh; Sarvestani, Fatemeh Sabet; Kazemi, Sepehr; Semsar, Maryam

    2015-05-01

    Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke. The Mesenchymal stem cells were isolated from adult rat bone marrow and the neural stem cells were isolated from ganglion eminence of rat embryo 14 days. The Mesenchymal stem cells were injected 1 day after middle cerebral artery occlusion (MCAO) and the neural stem cells transplanted 7 day after MCAO. After 28 days, the neurological outcomes and brain lesion volumes were evaluated. Also, the activity of Caspase 3 was assessed in different groups. The group which received combination cell therapy had better neurological examination and less brain lesion. Also the combination cell therapy group had the least Caspase 3 activity among the groups. The combination cell therapy is more effective than Mesenchymal stem cell therapy and neural stem cell therapy separately in treating the brain stroke in rats.

  16. [Translational/regulatory science researches of NIHS for regenerative medicine and cellular therapy products].

    Science.gov (United States)

    Sato, Yoji

    2014-01-01

    In 2013, the Japanese Diet passed the Regenerative Medicine Promotion Act and the revisions to the Pharmaceutical Affairs Act, which was also renamed as the Therapeutic Products Act (TPA). One of the aims of the new/revised Acts is to promote the development and translation of and access to regenerative/cellular therapies. In the TPA, a product derived from processing cells is categorized as a subgroup of "regenerative medicine, cellular therapy and gene therapy products" (RCGPs), products distinct from pharmaceuticals and medical devices, allowing RCGPs to obtain a conditional and time- limited marketing authorization much earlier than that under the conventional system. To foster not only RCGPs, but also innovative pharmaceuticals and medical devices, the Ministry of Health, Labour and Welfare recently launched Translational Research Program for Innovative Pharmaceuticals, Medical Devices and RCGPs. This mini-review introduces contributions of the National Institute of Health Sciences (NIHS) to research projects on RCGPs in the Program.

  17. Health consumers and stem cell therapy innovation: markets, models and regulation.

    Science.gov (United States)

    Salter, Brian; Zhou, Yinhua; Datta, Saheli

    2014-05-01

    Global health consumer demand for stem cell therapies is vibrant, but the supply of treatments from the conventional science-based model of innovation is small and unlikely to increase in the near future. At the same time, several models of medical innovation have emerged that can respond to the demand, often employing a transnational value chain to deliver the product. Much of the commentary has approached the issue from a supply side perspective, demonstrating the extent to which national and transnational regulation fails to impose what are regarded as appropriate standards on the 'illicit' supply of stem cell therapies characterized by little data and poor outcomes. By contrast, this article presents a political economic analysis with a strong demand side perspective, arguing that the problem of what is termed 'stem cell tourism' is embedded in the demand-supply relationship of the health consumer market and its engagement with different types of stem cell therapy innovation. To be meaningful, discussions of regulation must recognize that analysis or risk being sidelined by a market, which ignores their often wishful thinking.

  18. Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy.

    Science.gov (United States)

    Ren, Jun; Gwin, William R; Zhou, Xinna; Wang, Xiaoli; Huang, Hongyan; Jiang, Ni; Zhou, Lei; Agarwal, Pankaj; Hobeika, Amy; Crosby, Erika; Hartman, Zachary C; Morse, Michael A; H Eng, Kevin; Lyerly, H Kim

    2017-01-01

    Purpose : Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods : We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results : Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions : Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

  19. Adult Stem Cell Therapy for Stroke: Challenges and Progress

    Science.gov (United States)

    Bang, Oh Young; Kim, Eun Hee; Cha, Jae Min; Moon, Gyeong Joon

    2016-01-01

    Stroke is one of the leading causes of death and physical disability among adults. It has been 15 years since clinical trials of stem cell therapy in patients with stroke have been conducted using adult stem cells like mesenchymal stem cells and bone marrow mononuclear cells. Results of randomized controlled trials showed that adult stem cell therapy was safe but its efficacy was modest, underscoring the need for new stem cell therapy strategies. The primary limitations of current stem cell therapies include (a) the limited source of engraftable stem cells, (b) the presence of optimal time window for stem cell therapies, (c) inherited limitation of stem cells in terms of growth, trophic support, and differentiation potential, and (d) possible transplanted cell-mediated adverse effects, such as tumor formation. Here, we discuss recent advances that overcome these hurdles in adult stem cell therapy for stroke. PMID:27733032

  20. Cell-Based Therapy

    Directory of Open Access Journals (Sweden)

    Masaaki Kitada

    2012-01-01

    Full Text Available Cell transplantation is a strategy with great potential for the treatment of Parkinson's disease, and many types of stem cells, including neural stem cells and embryonic stem cells, are considered candidates for transplantation therapy. Mesenchymal stem cells are a great therapeutic cell source because they are easy accessible and can be expanded from patients or donor mesenchymal tissues without posing serious ethical and technical problems. They have trophic effects for protecting damaged tissues as well as differentiation ability to generate a broad spectrum of cells, including dopamine neurons, which contribute to the replenishment of lost cells in Parkinson's disease. This paper focuses mainly on the potential of mesenchymal stem cells as a therapeutic cell source and discusses their potential clinical application in Parkinson's disease.

  1. [The certification of advanced therapy medicinal products. A quality label for product development in small and medium-sized enterprises].

    Science.gov (United States)

    Berger, A; Schüle, S; Flory, E

    2011-07-01

    Advanced therapy medicinal products (ATMPs) are gene therapy, cell therapy, and tissue engineered products. To gain access to the market within the European Union, ATMPs must be authorized by the European Commission (EC). Especially for small and medium-sized enterprises (SMEs), the European centralized procedure of marketing authorization that is conducted by the European Medicines Agency (EMA) constitutes a major challenge, because SMEs often have little experience with regulatory procedures and many have limited financial possibilities. To tackle these challenges, a certification procedure exclusively for SMEs and their ATMP development was introduced by the EC. Independently from a marketing authorization application, development and/or production processes can be certified. An issued certificate demonstrates that the respective process meets the current regulatory and scientific requirements of the EMA, representing a valuable milestone for putative investors and licensees. This article highlights the background, the detailed procedure, the minimum requirements, as well as the costs of certification, while giving further noteworthy guidance for interested parties.

  2. Manufacturing models permitting roll out/scale out of clinically led autologous cell therapies: regulatory and scientific challenges for comparability.

    Science.gov (United States)

    Hourd, Paul; Ginty, Patrick; Chandra, Amit; Williams, David J

    2014-08-01

    Manufacturing of more-than-minimally manipulated autologous cell therapies presents a number of unique challenges driven by complex supply logistics and the need to scale out production to multiple manufacturing sites or near the patient within hospital settings. The existing regulatory structure in Europe and the United States imposes a requirement to establish and maintain comparability between sites. Under a single market authorization, this is likely to become an unsurmountable burden beyond two or three sites. Unless alternative manufacturing approaches can be found to bridge the regulatory challenge of comparability, realizing a sustainable and investable business model for affordable autologous cell therapy supply is likely to be extremely demanding. Without a proactive approach by the regulators to close this "translational gap," these products may not progress down the development pipeline, threatening patient accessibility to an increasing number of clinician-led autologous cellular therapies that are already demonstrating patient benefits. We propose three prospective manufacturing models for the scale out/roll out of more-than-minimally manipulated clinically led autologous cell therapy products and test their prospects for addressing the challenge of product comparability with a selected expert reference panel of US and UK thought leaders. This paper presents the perspectives and insights of the panel and identifies where operational, technological and scientific improvements should be prioritized. The main purpose of this report is to solicit feedback and seek input from key stakeholders active in the field of autologous cell therapy in establishing a consensus-based manufacturing approach that may permit the roll out of clinically led autologous cell therapies. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Perspectives of Stem Cell-Based Therapy for Age-Related Retinal Degenerative Diseases.

    Science.gov (United States)

    Holan, Vladimir; Hermankova, Barbora; Kossl, Jan

    2017-09-01

    Retinal degenerative diseases, which include age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and glaucoma, mostly affect the elderly population and are the most common cause of decreased quality of vision or even blindness. So far, there is no satisfactory treatment protocol to prevent, stop, or cure these disorders. A great hope and promise for patients suffering from retinal diseases is represented by stem cell-based therapy that could replace diseased or missing retinal cells and support regeneration. In this respect, mesenchymal stem cells (MSCs) that can be obtained from the particular patient and used as autologous cells have turned out to be a promising stem cell type for treatment. Here we show that MSCs can differentiate into cells expressing markers of retinal cells, inhibit production of pro-inflammatory cytokines by retinal tissue, and produce a number of growth and neuroprotective factors for retinal regeneration. All of these properties make MSCs a prospective cell type for cell-based therapy of age-related retinal degenerative diseases.

  4. Stem cell therapy for inflammatory bowel disease

    NARCIS (Netherlands)

    Duijvestein, Marjolijn

    2012-01-01

    Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal

  5. Perspectives on Regulatory T Cell Therapies.

    Science.gov (United States)

    Probst-Kepper, Michael; Kröger, Andrea; Garritsen, Henk S P; Buer, Jan

    2009-01-01

    Adoptive transfer in animal models clearly indicate an essential role of CD4+ CD25+ FOXP3+ regulatory T (T(reg)) cells in prevention and treatment of autoimmune and graft-versus-host disease. Thus, T(reg) cell therapies and development of drugs that specifically enhance T(reg) cell function and development represent promising tools to establish dominant tolerance. So far, lack of specific markers to differentiate human T(reg) cells from activated CD4+ CD25+ effector T cells, which also express FOXP3 at different levels, hampered such an approach. Recent identification of the orphan receptor glycoprotein-A repetitions predominant (GARP or LRRC32) as T(reg) cell-specific key molecule that dominantly controls FOXP3 via a positive feedback loop opens up new perspectives for molecular and cellular therapies. This brief review focuses on the role of GARP as a safeguard of a complex regulatory network of human T(reg) cells and its implications for regulatory T cell therapies in autoimmunity and graft-versus-host disease.

  6. Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

    Science.gov (United States)

    Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

    2004-10-01

    An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated.

  7. Cell-based therapies and imaging in cardiology.

    Science.gov (United States)

    Bengel, Frank M; Schachinger, Volker; Dimmeler, Stefanie

    2005-12-01

    Cell therapy for cardiac repair has emerged as one of the most exciting and promising developments in cardiovascular medicine. Evidence from experimental and clinical studies is increasing that this innovative treatment will influence clinical practice in the future. But open questions and controversies with regard to the basic mechanisms of this therapy continue to exist and emphasise the need for specific techniques to visualise the mechanisms and success of therapy in vivo. Several non-invasive imaging approaches which aim at tracking of transplanted cells in the heart have been introduced. Among these are direct labelling of cells with radionuclides or paramagnetic agents, and the use of reporter genes for imaging of cell transplantation and differentiation. Initial studies have suggested that these molecular imaging techniques have great potential. Integration of cell imaging into studies of cardiac cell therapy holds promise to facilitate further growth of the field towards a broadly clinically useful application.

  8. Cell-based therapies and imaging in cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Bengel, Frank M. [Technische Universitaet Muenchen, Nuklearmedizinische Klinik und Poliklinik, Munich (Germany); Schachinger, Volker; Dimmeler, Stefanie [University of Frankfurt, Department of Molecular Cardiology, Frankfurt (Germany)

    2005-12-01

    Cell therapy for cardiac repair has emerged as one of the most exciting and promising developments in cardiovascular medicine. Evidence from experimental and clinical studies is increasing that this innovative treatment will influence clinical practice in the future. But open questions and controversies with regard to the basic mechanisms of this therapy continue to exist and emphasise the need for specific techniques to visualise the mechanisms and success of therapy in vivo. Several non-invasive imaging approaches which aim at tracking of transplanted cells in the heart have been introduced. Among these are direct labelling of cells with radionuclides or paramagnetic agents, and the use of reporter genes for imaging of cell transplantation and differentiation. Initial studies have suggested that these molecular imaging techniques have great potential. Integration of cell imaging into studies of cardiac cell therapy holds promise to facilitate further growth of the field towards a broadly clinically useful application. (orig.)

  9. Relationship between spermatogonial stem cell survival and testis function after cytotoxic therapy

    International Nuclear Information System (INIS)

    Meistrich, M.L.

    1986-01-01

    This review, with substantial bibliography, concludes that the acute effects of radiation and cytotoxic drugs are a result of toxicity to the most sensitive of the germ cells, which in most cases are the differentiating spermatogonia. Long-term sterility or reduction in sperm production depends directly on killing of spermatogonial stem cells. For a variety of cytotoxic agents, the same relationship holds between the stem cell survival index and the prompt recovery level of sperm production (at 56 days), the maximal recovered level of sperm production, and the time required for fertility to return. It also appears that the spermatogonial stem cell is the target for long-term sterility in man following cytotoxic therapy. It is not known whether the delay in recovery is a result of this direct damage to the stem cell or an effect on another target cell in the tissue. Data obtained in both experimental animals and man indicate very little direct changes in the secretory cells and other stromal cells of the testis, and there is no evidence as yet that any alterations in these cells adversely affect sperm production or reproductive performance. (UK)

  10. Full GMP-Compliant Validation of Bone Marrow-Derived Human CD133+ Cells as Advanced Therapy Medicinal Product for Refractory Ischemic Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Daniela Belotti

    2015-01-01

    Full Text Available According to the European Medicine Agency (EMA regulatory frameworks, Advanced Therapy Medicinal Products (ATMP represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133+ cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs. In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM, ATMP-CD133 manufacturing output yielded a median of 6.66 × 106 of CD133+ cells (range 2.85 × 106–30.84 × 106, with a viability ranged between 96,03% and 99,97% (median 99,87% and a median purity of CD133+ cells of 90,60% (range 81,40%–96,20%. Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 106 cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial.

  11. Full GMP-compliant validation of bone marrow-derived human CD133(+) cells as advanced therapy medicinal product for refractory ischemic cardiomyopathy.

    Science.gov (United States)

    Belotti, Daniela; Gaipa, Giuseppe; Bassetti, Beatrice; Cabiati, Benedetta; Spaltro, Gabriella; Biagi, Ettore; Parma, Matteo; Biondi, Andrea; Cavallotti, Laura; Gambini, Elisa; Pompilio, Giulio

    2015-01-01

    According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133(+) cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 10(6) of CD133(+) cells (range 2.85 × 10(6)-30.84 × 10(6)), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133(+) cells of 90,60% (range 81,40%-96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 10(6) cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial).

  12. Full GMP-Compliant Validation of Bone Marrow-Derived Human CD133+ Cells as Advanced Therapy Medicinal Product for Refractory Ischemic Cardiomyopathy

    Science.gov (United States)

    Belotti, Daniela; Gaipa, Giuseppe; Bassetti, Beatrice; Cabiati, Benedetta; Spaltro, Gabriella; Biagi, Ettore; Parma, Matteo; Biondi, Andrea; Cavallotti, Laura; Gambini, Elisa; Pompilio, Giulio

    2015-01-01

    According to the European Medicine Agency (EMA) regulatory frameworks, Advanced Therapy Medicinal Products (ATMP) represent a new category of drugs in which the active ingredient consists of cells, genes, or tissues. ATMP-CD133 has been widely investigated in controlled clinical trials for cardiovascular diseases, making CD133+ cells one of the most well characterized cell-derived drugs in this field. To ensure high quality and safety standards for clinical use, the manufacturing process must be accomplished in certified facilities following standard operative procedures (SOPs). In the present work, we report the fully compliant GMP-grade production of ATMP-CD133 which aims to address the treatment of chronic refractory ischemic heart failure. Starting from bone marrow (BM), ATMP-CD133 manufacturing output yielded a median of 6.66 × 106 of CD133+ cells (range 2.85 × 106–30.84 × 106), with a viability ranged between 96,03% and 99,97% (median 99,87%) and a median purity of CD133+ cells of 90,60% (range 81,40%–96,20%). Based on these results we defined our final release criteria for ATMP-CD133: purity ≥ 70%, viability ≥ 80%, cellularity between 1 and 12 × 106 cells, sterile, and endotoxin-free. The abovementioned criteria are currently applied in our Phase I clinical trial (RECARDIO Trial). PMID:26495296

  13. Present and future of allogeneic natural killer cell therapy

    Directory of Open Access Journals (Sweden)

    Okjae eLim

    2015-06-01

    Full Text Available Natural killer (NK cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA-haploidentical hematopoietic stem cell transplantation revealed the anti-tumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor (KIR ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions.

  14. Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy.

    Science.gov (United States)

    Wei, Zheng Z; Zhu, Yan-Bing; Zhang, James Y; McCrary, Myles R; Wang, Song; Zhang, Yong-Bo; Yu, Shan-Ping; Wei, Ling

    2017-10-05

    Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues. This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation." Original articles and critical reviews on the topics were selected. Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified. In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

  15. PET imaging of adoptive progenitor cell therapies

    International Nuclear Information System (INIS)

    Gelovani, Juri G.

    2008-01-01

    The overall objective of this application is to develop novel technologies for non-invasive imaging of adoptive stem cell-based therapies with positron emission tomography (PET) that would be applicable to human patients. To achieve this objective, stem cells will be genetically labeled with a PET-reporter gene and repetitively imaged to assess their distribution, migration, differentiation, and persistence using a radiolabeled reporter probe. This new imaging technology will be tested in adoptive progenitor cell-based therapy models in animals, including: delivery pro-apoptotic genes to tumors, and T-cell reconstitution for immunostimulatory therapy during allogeneic bone marrow progenitor cell transplantation. Technical and Scientific Merits. Non-invasive whole body imaging would significantly aid in the development and clinical implementation of various adoptive progenitor cell-based therapies by providing the means for non-invasive monitoring of the fate of injected progenitor cells over a long period of observation. The proposed imaging approaches could help to address several questions related to stem cell migration and homing, their long-term viability, and their subsequent differentiation. The ability to image these processes non-invasively in 3D and repetitively over a long period of time is very important and will help the development and clinical application of various strategies to control and direct stem cell migration and differentiation. Approach to accomplish the work. Stem cells will be genetically with a reporter gene which will allow for repetitive non-invasive 'tracking' of the migration and localization of genetically labeled stem cells and their progeny. This is a radically new approach that is being developed for future human applications and should allow for a long term (many years) repetitive imaging of the fate of tissues that develop from the transplanted stem cells. Why the approach is appropriate. The novel approach to stem cell imaging

  16. PET imaging of adoptive progenitor cell therapies.

    Energy Technology Data Exchange (ETDEWEB)

    Gelovani, Juri G.

    2008-05-13

    Objectives. The overall objective of this application is to develop novel technologies for non-invasive imaging of adoptive stem cell-based therapies with positron emission tomography (PET) that would be applicable to human patients. To achieve this objective, stem cells will be genetically labeled with a PET-reporter gene and repetitively imaged to assess their distribution, migration, differentiation, and persistence using a radiolabeled reporter probe. This new imaging technology will be tested in adoptive progenitor cell-based therapy models in animals, including: delivery pro-apoptotic genes to tumors, and T-cell reconstitution for immunostimulatory therapy during allogeneic bone marrow progenitor cell transplantation. Technical and Scientific Merits. Non-invasive whole body imaging would significantly aid in the development and clinical implementation of various adoptive progenitor cell-based therapies by providing the means for non-invasive monitoring of the fate of injected progenitor cells over a long period of observation. The proposed imaging approaches could help to address several questions related to stem cell migration and homing, their long-term viability, and their subsequent differentiation. The ability to image these processes non-invasively in 3D and repetitively over a long period of time is very important and will help the development and clinical application of various strategies to control and direct stem cell migration and differentiation. Approach to accomplish the work. Stem cells will be genetically with a reporter gene which will allow for repetitive non-invasive “tracking” of the migration and localization of genetically labeled stem cells and their progeny. This is a radically new approach that is being developed for future human applications and should allow for a long term (many years) repetitive imaging of the fate of tissues that develop from the transplanted stem cells. Why the approach is appropriate. The novel approach to

  17. Counter-flow elutriation of clinical peripheral blood mononuclear cell concentrates for the production of dendritic and T cell therapies

    OpenAIRE

    Stroncek, David F; Fellowes, Vicki; Pham, Chauha; Khuu, Hanh; Fowler, Daniel H; Wood, Lauren V; Sabatino, Marianna

    2014-01-01

    Introduction Peripheral blood mononuclear cells (PBMC) concentrates collected by apheresis are frequently used as starting material for cellular therapies, but the cell of interest must often be isolated prior to initiating manufacturing. Study design and methods The results of enriching 59 clinical PBMC concentrates for monocytes or lymphocytes from patients with solid tumors or multiple myeloma using a commercial closed system semi-automated counter-flow elutriation instrument (Elutra, Teru...

  18. Cell banking for regulatory T cell-based therapy: strategies to overcome the impact of cryopreservation on the Treg viability and phenotype.

    Science.gov (United States)

    Gołąb, Karolina; Grose, Randall; Placencia, Veronica; Wickrema, Amittha; Solomina, Julia; Tibudan, Martin; Konsur, Evelyn; Ciepły, Kamil; Marek-Trzonkowska, Natalia; Trzonkowski, Piotr; Millis, J Michael; Fung, John; Witkowski, Piotr

    2018-02-09

    The first clinical trials with adoptive Treg therapy have shown safety and potential efficacy. Feasibility of such therapy could be improved if cells are cryopreserved and stored until optimal timing for infusion. Herein, we report the evaluation of two cell-banking strategies for Treg therapy: 1) cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and 2) cryopreservation of ex-vivo expanded Tregs (CD4 + CD25 hi CD127 lo/- cells). First, we checked how cryopreservation affects cell viability and Treg markers expression. Then, we performed Treg isolation/expansion with the final products release testing. We observed substantial decrease in cell number recovery after thawing and overnight culture. This observation might be explained by the high percentage of necrotic and apoptotic cells found just after thawing. Furthermore, we noticed fluctuations in percentage of CD4 + CD25 hi CD127 - and CD4 + FoxP3 + cells obtained from cryopreserved CD4 + as well as Treg cells. However, after re-stimulation Tregs expanded well, presented a stable phenotype and fulfilled the release criteria at the end of expansions. Cryopreservation of CD4 + cells for subsequent Treg isolation/expansion and cryopreservation of expanded Tregs with re-stimulation and expansion after thawing, are promising solutions to overcome detrimental effects of cryopreservation. Both of these cell-banking strategies for Treg therapy can be applied when designing new clinical trials.

  19. Stem Cell Therapy: An emerging science

    International Nuclear Information System (INIS)

    Khan, Muhammad M.

    2007-01-01

    The research on stem cells is advancing knowledge about the development of an organism from a single cell and to how healthy cells replace damaged cells in adult organisms. Stem cell therapy is emerging rapidly nowadays as a technical tool for tissue repair and replacement. The purpose of this review to provide a framework of understanding for the challenges behind translating fundamental stem cell biology and its potential use into clinical therapies, also to give an overview on stem cell research to the scientists of Saudi Arabia in general. English language MEDLINE publications from 1980 through January 2007 for experimental, observational and clinical studies having relation with stem cells with different diseases were reviewed. Approximately 85 publications were reviewed based on the relevance, strength and quality of design and methods, 36 publications were selected for inclusion. Stem cells reside in a specific area of each tissue where they may remain undivided for several years until they are activated by disease or tissue injury. The embryonic stem cells are typically derived from four or five days old embryos and they are pluripotent. The adult tissues reported to contain stem cells brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin and liver. The promise of stem cell therapies is an exciting one, but significant technical hurdles remain that will only be overcome through years of intensive research. (author)

  20. Effects of concomitant temozolomide and radiation therapies on WT1-specific T-cells in malignant glioma

    International Nuclear Information System (INIS)

    Chiba, Yasuyoshi; Hashimoto, Naoya; Tsuboi, Akihiro

    2010-01-01

    Immunotherapy targeting the Wilms' tumour 1 gene product has been proven safe and effective for treating malignant glioma in a phase II clinical study. Currently, radiation/temozolomide therapy is the standard treatment with only modest benefit. Whether combining radiation/temozolomide therapy with WT1 immunotherapy will have a negating effect on immunotherapy is still controversial because of the significant lymphocytopaenia induced by the former therapy. To address this issue, we investigated the changes in frequency and number of WT1-specific T-cells in patients with malignant gliomas. Twenty-two patients with newly diagnosed malignant glioma who received standard radiation/temozolomide therapy were recruited for the study. Blood samples were collected before treatment and on the sixth week of therapy. The frequencies and numbers of lymphocytes, CD8 + T-cells, WT1-specific T-cells, regulatory T-cells, natural killer cells and natural killer T-cells were measured and analysed using T-tests. Analysis of the frequency of T lymphocytes and its subpopulation showed an increase in regulatory T-cells, but no significant change was noted in the populations of T-cells, WT1-specific T-cells, natural killer (NK) cells and natural killer T (NKT) cells. Reductions in the total numbers of T-cells, WT1-specific T-cells, NK cells and NKT cells were mainly a consequence of the decrease in the total lymphocyte count. Radiation/temozolomide therapy did not significantly affect the frequency of WT1-specific T-cells, suggesting that the combination with WT1 immunotherapy may be possible, although further assessment in the clinical setting is warranted. (author)

  1. Analysis of cell line variation in biochemical production of protoporphyrin IX

    Science.gov (United States)

    Gibbs, Summer L.; Chen, Bin; O'Hara, Julia A.; Hoopes, P. Jack; Hasan, Tayyaba; Pogue, Brian W.

    2006-02-01

    Protoporphyrin IX (PpIX) is produced via the heme synthesis pathway by the cell following administration of aminolevulinic acid (ALA). ALA synthase, the enzyme that produces ALA in the cell from glycine and succinyl-coenzyme A, is inhibited in a feedback mechanism by heme and thus is the rate limiting enzyme in the heme synthesis pathway. Since ALA is administered systemically, the rate limiting step that naturally exists in the cells is bypassed, however it is currently unclear why cells have different rate limiting steps in the ALA-PpIX synthesis pathway, and more specifically which types of cancer cells are most productive. It has been determined that when the same amount of ALA is administered to a wide panel of cancer cells in vitro that vastly differing amounts of PpIX are produced. The steps for the ALA-PpIX pathway occur in and around the mitochondria of the cell, but interestingly no correlation is seen between PpIX production and mitochondrial content of the cell, following ALA administration. However, total cell area shows positive correlation with PpIX production. Administration of the iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone (L1) in combination with ALA allows the final step in the heme synthesis pathway, conversion of PpIX to heme, to be delayed and thus increases the detectable amount of PpIX in each cell line. The cell lines that have the lowest PpIX production following administration of ALA alone show the largest increase in production following the combined administration of ALA and L1. PpIX fluorescence is thought to be a measure of cellular activity and the goal of the current study was to determine which cell lines would be the most promising targets for fluorescence detection or monitoring response to therapy. The results indicate that the cells with larger size and larger numbers of mitochondria may be good potential targets for this therapy. While this conclusion may appear obvious, it is not universally true, and cellular specific

  2. Stem Cell Therapy for Neonatal Hypoxic-Ischemic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Gabriel eGonzales-Portillo

    2014-08-01

    Full Text Available Treatments for neonatal hypoxic ischemic encephalopathy (HIE have been limited. The aim of this paper is to offer translational research guidance on stem cell therapy for neonatal HIE by examining clinically relevant animal models, practical stem cell sources, safety and efficacy of endpoint assays, as well as a general understanding of modes of action of this cellular therapy. In order to do so, we discuss the clinical manifestations of HIE, highlighting its overlapping pathologies with stroke providing insights on the potential of cell therapy, currently investigated in stroke, for HIE. To this end, we draw guidance from recommendations outlined in Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS, which have been recently modified to Baby STEPS to cater for the neonatal symptoms of HIE. These guidelines recognized that neonatal HIE exhibits distinct disease symptoms from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, new information about recent clinical trials, and insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with HIE.

  3. Combination stem cell therapy for heart failure

    Directory of Open Access Journals (Sweden)

    Ichim Thomas E

    2010-04-01

    Full Text Available Abstract Patients with congestive heart failure (CHF that are not eligible for transplantation have limited therapeutic options. Stem cell therapy such as autologous bone marrow, mobilized peripheral blood, or purified cells thereof has been used clinically since 2001. To date over 1000 patients have received cellular therapy as part of randomized trials, with the general consensus being that a moderate but statistically significant benefit occurs. Therefore, one of the important next steps in the field is optimization. In this paper we discuss three ways to approach this issue: a increasing stem cell migration to the heart; b augmenting stem cell activity; and c combining existing stem cell therapies to recapitulate a "therapeutic niche". We conclude by describing a case report of a heart failure patient treated with a combination stem cell protocol in an attempt to augment beneficial aspects of cord blood CD34 cells and mesenchymal-like stem cells.

  4. Two different approaches in skin cancer therapy: using a photosensitizer/a natural product

    Science.gov (United States)

    Abraham, Annie; Gayathri, Devi D.; Cibin, T. R.; Ramaiah, D.

    2010-02-01

    This paper deals with two potential modes for the treatment of skin cancer-one a novel approach using a squaraine dye and the other using a natural product- the flavonoid fraction of Saraca asoka. Squaraine dye is a photosensitizing agent, which is preferentially taken up and retained by the tumor cells and when irradiated with high power visible light results in the selective destruction of the tumor cells by photodynamic therapy. The uniqueness of this mode of treatment lies in the selective destruction of tumor cells without affecting the neighbouring normal cells, which is much advantageous over radiation therapy now frequently used. The chemopreventive and therapeutic effects of the plant component are explored as well. The experimental models were Swiss albino mice in which skin tumor was induced by DMBA. Marked reduction in tumor volume and burden in the treated groups were observed. The reversal of biochemical enzyme markers like rhodanese, myeloperoxidase, β-D glucuronidase, lactate dehydrogenase, hexokinase and sialic acid to near normal levels were observed in the PDT and flavonoid fraction treated groups. The live photographs of the experimental animals and histopathological data further support the obtained results. The study assumes importance as it combines a traditional treatment mode and a novel aspect in cancer therapy using the same experimental models. Also this is the first report on PDT using a squaraine dye for skin cancer therapy in vivo.

  5. Challenges for heart disease stem cell therapy

    Directory of Open Access Journals (Sweden)

    Hoover-Plow J

    2012-02-01

    Full Text Available Jane Hoover-Plow, Yanqing GongDepartments of Cardiovascular Medicine and Molecular Cardiology, Joseph J Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USAAbstract: Cardiovascular diseases (CVDs are the leading cause of death worldwide. The use of stem cells to improve recovery of the injured heart after myocardial infarction (MI is an important emerging therapeutic strategy. However, recent reviews of clinical trials of stem cell therapy for MI and ischemic heart disease recovery report that less than half of the trials found only small improvements in cardiac function. In clinical trials, bone marrow, peripheral blood, or umbilical cord blood cells were used as the source of stem cells delivered by intracoronary infusion. Some trials administered only a stem cell mobilizing agent that recruits endogenous sources of stem cells. Important challenges to improve the effectiveness of stem cell therapy for CVD include: (1 improved identification, recruitment, and expansion of autologous stem cells; (2 identification of mobilizing and homing agents that increase recruitment; and (3 development of strategies to improve stem cell survival and engraftment of both endogenous and exogenous sources of stem cells. This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.Keywords: mobilization, expansion, homing, survival, engraftment

  6. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells.

    Science.gov (United States)

    Levine, B L

    2015-03-01

    Performance enhancement of the immune system can now be generated through ex vivo gene modification of T cells in order to redirect native specificity to target tumor antigens. This approach combines the specificity of antibody therapy, the expanded response of cellular therapy and the memory activity of vaccine therapy. Recent clinical trials of chimeric antigen receptor (CAR) T cells directed toward CD19 as a stand-alone therapy have shown sustained complete responses in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. As these drug products are individually derived from a patient's own cells, a different manufacturing approach is required for this kind of personalized therapy compared with conventional drugs. Key steps in the CAR T-cell manufacturing process include the selection and activation of isolated T cells, transduction of T cells to express CARs, ex vivo expansion of modified T cells and cryopreservation in infusible media. In this review, the steps involved in isolating, genetically modifying and scaling-out the CAR T cells for use in a clinical setting are described in the context of in-process and release testing and regulatory standards.

  7. Investigation progress of imaging techniques monitoring stem cell therapy

    International Nuclear Information System (INIS)

    Wu Jun; An Rui

    2006-01-01

    Recently stem cell therapy has showed potential clinical application in diabetes mellitus, cardiovascular diseases, malignant tumor and trauma. Efficient techniques of non-invasively monitoring stem cell transplants will accelerate the development of stem cell therapies. This paper briefly reviews the clinical practice of stem cell, in addition, makes a review of monitoring methods including magnetic resonance and radionuclide imaging which have been used in stem cell therapy. (authors)

  8. Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in-situ targeting of dendritic cells.

    Science.gov (United States)

    Morelli, Adrian E; Thomson, Angus W

    2014-08-01

    Extensive research in murine transplant models over the past two decades has convincingly demonstrated the ability of regulatory dendritic cells (DCregs) to promote long-term allograft survival. We review important considerations regarding the source of therapeutic DCregs (donor or recipient) and their mode of action, in-situ targeting of DCregs, and optimal therapeutic regimens to promote DCreg function. Recent studies have defined protocols and mechanisms whereby ex-vivo-generated DCregs of donor or recipient origin subvert allogeneic T-cell responses and promote long-term organ transplant survival. Particular interest has focused on how donor antigen is acquired, processed and presented by autologous dendritic cells, on the stability of DCregs, and on in-situ targeting of dendritic cells to promote their tolerogenic function. New evidence of the therapeutic efficacy of DCregs in a clinically relevant nonhuman primate organ transplant model and production of clinical grade DCregs support early evaluation of DCreg therapy in human graft recipients. We discuss strategies currently used to promote dendritic cell tolerogenicity, including DCreg therapy and in-situ targeting of dendritic cells, with a view to improved understanding of underlying mechanisms and identification of the most promising strategies for therapeutic application.

  9. Modulation of NO and ROS production by AdiNOS transduced vascular cells through supplementation with L-Arg and BH4: implications for gene therapy of restenosis.

    Science.gov (United States)

    Forbes, Scott P; Alferiev, Ivan S; Chorny, Michael; Adamo, Richard F; Levy, Robert J; Fishbein, Ilia

    2013-09-01

    Gene therapy with viral vectors encoding for NOS enzymes has been recognized as a potential therapeutic approach for the prevention of restenosis. Optimal activity of iNOS is dependent on the intracellular availability of L-Arg and BH4 via prevention of NOS decoupling and subsequent ROS formation. Herein, we investigated the effects of separate and combined L-Arg and BH4 supplementation on the production of NO and ROS in cultured rat arterial smooth muscle and endothelial cells transduced with AdiNOS, and their impact on the antirestenotic effectiveness of AdiNOS delivery to balloon-injured rat carotid arteries. Supplementation of AdiNOS transduced endothelial and vascular smooth muscle cells with L-Arg (3.0 mM), BH4 (10 μM) and especially their combination resulted in a significant increase in NO production as measured by nitrite formation in media. Formation of ROS was dose-dependently increased following transduction with increasing MOIs of AdiNOS. Exposure of RASMC to AdiNOS tethered to meshes via a hydrolyzable cross-linker, modeling viral delivery from stents, resulted in increased ROS production, which was decreased by supplementation with BH4 but not L-Arg or L-Arg/BH4. Enhanced cell death, caused by AdiNOS transduction, was also preventable with BH4 supplementation. In the rat carotid model of balloon injury, intraluminal delivery of AdiNOS in BH4-, L-Arg-, and especially in BH4 and L-Arg supplemented animals was found to significantly enhance the antirestenotic effects of AdiNOS-mediated gene therapy. Fine-tuning of iNOS function by L-Arg and BH4 supplementation in the transduced vasculature augments the therapeutic potential of gene therapy with iNOS for the prevention of restenosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Stem cell therapy for inflammatory bowel disease

    OpenAIRE

    Duijvestein, Marjolijn

    2012-01-01

    Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal antigens. MSCs have the capacity to differentiate into a wide variety of distinct cell lineages and to suppress immune responses in vitro and in vivo. The main goal of this thesis was to study the s...

  11. Stem cell route to neuromuscular therapies.

    Science.gov (United States)

    Partridge, Terence A

    2003-02-01

    As applied to skeletal muscle, stem cell therapy is a reincarnation of myoblast transfer therapy that has resulted from recent advances in the cell biology of skeletal muscle. Both strategies envisage the reconstruction of damaged muscle from its precursors, but stem cell therapy employs precursors that are earlier in the developmental hierarchy. It is founded on demonstrations of apparently multipotential cells in a wide variety of tissues that can assume, among others, a myogenic phenotype. The main demonstrated advantage of such cells is that they are capable of colonizing many tissues, including skeletal and cardiac muscle via the blood vascular system, thereby providing the potential for a body-wide distribution of myogenic progenitors. From a practical viewpoint, the chief disadvantage is that such colonization has been many orders of magnitude too inefficient to be useful. Proposals for overcoming this drawback are the subject of much speculation but, so far, relatively little experimentation. This review attempts to give some perspective to the status of the stem cell as a therapeutic instrument for neuromuscular disease and to identify issues that need to be addressed for application of this technology.

  12. Stem Cell Therapy for Erectile Dysfunction.

    Science.gov (United States)

    Matz, Ethan L; Terlecki, Ryan; Zhang, Yuanyuan; Jackson, John; Atala, Anthony

    2018-04-06

    The prevalence of erectile dysfunction (ED) is substantial and continues to rise. Current therapeutics for ED consist of oral medications, intracavernosal injections, vacuum erection devices, and penile implants. While such options may manage the disease state, none of these modalities, however, restore function. Stem cell therapy has been evaluated for erectile restoration in animal models. These cells have been derived from multiple tissues, have varied potential, and may function via local engraftment or paracrine signaling. Bone marrow-derived stem cells (BMSC) and adipose-derived stem cells (ASC) have both been used in these models with noteworthy effects. Herein, we will review the pathophysiology of ED, animal models, current and novel stem-cell based therapeutics, clinical trials and areas for future research. The relevant literature and contemporary data using keywords, "stem cells and erectile dysfunction" was reviewed. Examination of evidence supporting the association between erectile dysfunction and adipose derived stem cells, bone marrow derived stem cells, placental stem cells, urine stem cells and stem cell therapy respectively. Placental-derived stem cells and urine-derived stem cells possess many similar properties as BMSC and ASC, but the methods of acquisition are favorable. Human clinical trials have already demonstrated successful use of stem cells for improvement of erectile function. The future of stem cell research is constantly being evaluated, although, the evidence suggests a place for stem cells in erectile dysfunction therapeutics. Matz EL, Terlecki R, Zhang Y, et al. Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev 2018;XX:XXX-XXX. Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  13. Stem Cell Therapy in Wound Healing and Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2016-08-01

    a novel approach to many diseases. SUMMARY: Wound healing therapies continue to rapidly evolve, with advances in basic science and engineering research heralding the development of new therapies, as well as ways to modify existing treatments. Stem cell-based therapy is one of the most promising therapeutic concepts for wound healing. Advances in stem cell biology have enabled researchers and clinicians alike with access to cells capable of actively modulating the healing response.  KEYWORDS: wound healing, tissue regeneration, stem cells therapy

  14. Enrichment of human hematopoietic stem/progenitor cells facilitates transduction for stem cell gene therapy.

    Science.gov (United States)

    Baldwin, Kismet; Urbinati, Fabrizia; Romero, Zulema; Campo-Fernandez, Beatriz; Kaufman, Michael L; Cooper, Aaron R; Masiuk, Katelyn; Hollis, Roger P; Kohn, Donald B

    2015-05-01

    Autologous hematopoietic stem cell (HSC) gene therapy for sickle cell disease has the potential to treat this illness without the major immunological complications associated with allogeneic transplantation. However, transduction efficiency by β-globin lentiviral vectors using CD34-enriched cell populations is suboptimal and large vector production batches may be needed for clinical trials. Transducing a cell population more enriched for HSC could greatly reduce vector needs and, potentially, increase transduction efficiency. CD34(+) /CD38(-) cells, comprising ∼1%-3% of all CD34(+) cells, were isolated from healthy cord blood CD34(+) cells by fluorescence-activated cell sorting and transduced with a lentiviral vector expressing an antisickling form of beta-globin (CCL-β(AS3) -FB). Isolated CD34(+) /CD38(-) cells were able to generate progeny over an extended period of long-term culture (LTC) compared to the CD34(+) cells and required up to 40-fold less vector for transduction compared to bulk CD34(+) preparations containing an equivalent number of CD34(+) /CD38(-) cells. Transduction of isolated CD34(+) /CD38(-) cells was comparable to CD34(+) cells measured by quantitative PCR at day 14 with reduced vector needs, and average vector copy/cell remained higher over time for LTC initiated from CD34(+) /38(-) cells. Following in vitro erythroid differentiation, HBBAS3 mRNA expression was similar in cultures derived from CD34(+) /CD38(-) cells or unfractionated CD34(+) cells. In vivo studies showed equivalent engraftment of transduced CD34(+) /CD38(-) cells when transplanted in competition with 100-fold more CD34(+) /CD38(+) cells. This work provides initial evidence for the beneficial effects from isolating human CD34(+) /CD38(-) cells to use significantly less vector and potentially improve transduction for HSC gene therapy. © 2015 AlphaMed Press.

  15. [Safety monitoring of cell-based medicinal products (CBMPs)].

    Science.gov (United States)

    Funk, Markus B; Frech, Marion; Spranger, Robert; Keller-Stanislawski, Brigitte

    2015-11-01

    Cell-based medicinal products (CBMPs), a category of advanced-therapy medicinal products (ATMPs), are authorised for the European market by the European Commission by means of the centralized marketing authorisation. By conforming to the German Medicinal Products Act (Sec. 4b AMG), national authorisation can be granted by the Paul-Ehrlich-Institut in Germany exclusively for ATMPs not based on a routine manufacturing procedure. In both procedures, quality, efficacy, and safety are evaluated and the risk-benefit balance is assessed. For the centralised procedure, mainly controlled clinical trial data must be submitted, whereas the requirements for national procedures could be modified corresponding to the stage of development of the ATMP. After marketing authorization, the marketing authorization/license holder is obligated to report all serious adverse reactions to the competent authority and to provide periodic safety update reports. If necessary, post-authorization safety studies could be imposed. On the basis of these regulatory measures, the safety of advanced therapies can be monitored and improved.

  16. Cancer stem cells, cancer cell plasticity and radiation therapy.

    Science.gov (United States)

    Vlashi, Erina; Pajonk, Frank

    2015-04-01

    Since the first prospective identification of cancer stem cells in solid cancers the cancer stem cell hypothesis has reemerged as a research topic of increasing interest. It postulates that solid cancers are organized hierarchically with a small number of cancer stem cells driving tumor growth, repopulation after injury and metastasis. They give rise to differentiated progeny, which lack these features. The model predicts that for any therapy to provide cure, all cancer stem cells have to be eliminated while the survival of differentiated progeny is less critical. In this review we discuss recent reports challenging the idea of a unidirectional differentiation of cancer cells. These reports provide evidence supporting the idea that non-stem cancer cells exhibit a remarkable degree of plasticity that allows them to re-acquire cancer stem cell traits, especially in the context of radiation therapy. We summarize conditions under which differentiation is reversed and discuss the current knowledge of the underlying mechanisms. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Stem cells: sources and therapies

    Directory of Open Access Journals (Sweden)

    Manuela Monti

    2012-01-01

    Full Text Available The historical, lexical and conceptual issues embedded in stem cell biology are reviewed from technical, ethical, philosophical, judicial, clinical, economic and biopolitical perspectives. The mechanisms assigning the simultaneous capacity to self-renew and to differentiate to stem cells (immortal template DNA and asymmetric division are evaluated in the light of the niche hypothesis for the stemness state. The induction of cell pluripotency and the different stem cells sources are presented (embryonic, adult and cord blood. We highlight the embryonic and adult stem cell properties and possible therapies while we emphasize the particular scientific and social values of cord blood donation to set up cord blood banks. The current scientific and legal frameworks of cord blood banks are reviewed at an international level as well as allogenic, dedicated and autologous donations. The expectations and the challenges in relation to present-day targeted diseases like diabetes mellitus type I, Parkinson's disease and myocardial infarction are evaluated in the light of the cellular therapies for regenerative medicine.

  18. Qualification of academic facilities for small-scale automated manufacture of autologous cell-based products.

    Science.gov (United States)

    Hourd, Paul; Chandra, Amit; Alvey, David; Ginty, Patrick; McCall, Mark; Ratcliffe, Elizabeth; Rayment, Erin; Williams, David J

    2014-01-01

    Academic centers, hospitals and small companies, as typical development settings for UK regenerative medicine assets, are significant contributors to the development of autologous cell-based therapies. Often lacking the appropriate funding, quality assurance heritage or specialist regulatory expertise, qualifying aseptic cell processing facilities for GMP compliance is a significant challenge. The qualification of a new Cell Therapy Manufacturing Facility with automated processing capability, the first of its kind in a UK academic setting, provides a unique demonstrator for the qualification of small-scale, automated facilities for GMP-compliant manufacture of autologous cell-based products in these settings. This paper shares our experiences in qualifying the Cell Therapy Manufacturing Facility, focusing on our approach to streamlining the qualification effort, the challenges, project delays and inefficiencies we encountered, and the subsequent lessons learned.

  19. Aging and stem cell therapy: AMPK as an applicable pharmacological target for rejuvenation of aged stem cells and achieving higher efficacy in stem cell therapy.

    Science.gov (United States)

    Khorraminejad-Shirazi, Mohammadhossein; Farahmandnia, Mohammad; Kardeh, Bahareh; Estedlal, Alireza; Kardeh, Sina; Monabati, Ahmad

    2017-10-19

    In recent years, tissue regeneration has become a promising field for developing stem cell-based transplantation therapies for human patients. Adult stem cells are affected by the same aging mechanisms that involve somatic cells. One of the mechanisms involved in cellular aging is hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and disruption of 5' adenosine monophosphate-activated protein kinase (AMPK). Aging of stem cells results in their impaired regenerative capacity and depletion of stem cell pools in adult tissue, which results in lower efficacy of stem cell therapy. By utilizing an effective therapeutic intervention for aged stem cells, stem cell therapy can become more promising for future application. mTORC1 inhibition is a practical approach to preserve the stem cell pool. In this article, we review the dynamic interaction between sirtuin (silent mating type information regulation 2 homolog) 1, AMPK, and mTORC1. We propose that using AMPK activators such as 5-aminoimidazole-4-carboxamide ribonucleotide, A769662, metformin, and oxidized nicotinamide adenine dinucleotide (NAD + ) are practical ways to be employed for achieving better optimized results in stem cell-based transplantation therapies. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

  20. Global Regulatory Differences for Gene- and Cell-Based Therapies

    DEFF Research Database (Denmark)

    Coppens, Delphi G M; De Bruin, Marie L; Leufkens, Hubert G M

    2017-01-01

    Gene- and cell-based therapies (GCTs) offer potential new treatment options for unmet medical needs. However, the use of conventional regulatory requirements for medicinal products to approve GCTs may impede patient access and therapeutic innovation. Furthermore, requirements differ between...... jurisdictions, complicating the global regulatory landscape. We provide a comparative overview of regulatory requirements for GCT approval in five jurisdictions and hypothesize on the consequences of the observed global differences on patient access and therapeutic innovation....

  1. Cell-based therapy technology classifications and translational challenges

    Science.gov (United States)

    Mount, Natalie M.; Ward, Stephen J.; Kefalas, Panos; Hyllner, Johan

    2015-01-01

    Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future. PMID:26416686

  2. Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice.

    Science.gov (United States)

    Sun, Zhen; Gou, Wenyu; Kim, Do-Sung; Dong, Xiao; Strange, Charlie; Tan, Yu; Adams, David B; Wang, Hongjun

    2017-11-01

    The objective of this study was to assess the capacity of adipose-derived mesenchymal stem cells (ASCs) to mitigate disease progression in an experimental chronic pancreatitis mouse model. Chronic pancreatitis (CP) was induced in C57BL/6 mice by repeated ethanol and cerulein injection, and mice were then infused with 4 × 10 5 or 1 × 10 6 GFP + ASCs. Pancreas morphology, fibrosis, inflammation, and presence of GFP + ASCs in pancreases were assessed 2 weeks after treatment. We found that ASC infusion attenuated pancreatic damage, preserved pancreas morphology, and reduced pancreatic fibrosis and cell death. GFP + ASCs migrated to pancreas and differentiated into amylase + cells. In further confirmation of the plasticity of ASCs, ASCs co-cultured with acinar cells in a Transwell system differentiated into amylase + cells with increased expression of acinar cell-specific genes including amylase and chymoB1. Furthermore, culture of acinar or pancreatic stellate cell lines in ASC-conditioned medium attenuated ethanol and cerulein-induced pro-inflammatory cytokine production in vitro. Our data show that a single intravenous injection of ASCs ameliorated CP progression, likely by directly differentiating into acinar-like cells and by suppressing inflammation, fibrosis, and pancreatic tissue damage. These results suggest that ASC cell therapy has the potential to be a valuable treatment for patients with pancreatitis. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  3. Pro-angiogenic cell-based therapy for the treatment of ischemic cardiovascular diseases.

    Science.gov (United States)

    Silvestre, Jean-Sébastien

    2012-10-01

    Pro-angiogenic cell therapy has emerged as a promising option to treat patients with acute myocardial infarction or with critical limb ischemia. Exciting pre-clinical studies have prompted the initiation of numerous clinical trials based on administration of stem/progenitor cells with pro-angiogenic potential. Most of the clinical studies performed so far have used bone marrow-derived or peripheral blood-derived mononuclear cells and showed, overall, a modest but significant benefit on tissue remodeling and function in patients with ischemic diseases. These mixed results pave the way for the development of strategies to overcome the limitation of autologous cell therapy and to propose more efficient approaches. Such strategies include pretreatment of cells with activators to augment cell recruitment and survival in the ischemic target area and/or the improvement of cell functions such as their paracrine ability to release proangiogenic factors and vasoactive molecules. In addition, efforts should be directed towards stimulation of both angiogenesis and vessel maturation, the development of a composite product consisting of stem/progenitor cells encapsulated in a biomaterial and the use of additional sources of regenerative cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy

    International Nuclear Information System (INIS)

    Gopinath, P; Ghosh, Siddhartha Sankar; Gogoi, Sonit Kumar; Chattopadhyay, Arun

    2008-01-01

    The impact of manufactured nanomaterials on human health and the environment is a major concern for commercial use of nanotechnology based products. A judicious choice of selective usage, lower nanomaterial concentration and use in combination with conventional therapeutic materials may provide the best solution. For example, silver nanoparticles (Ag NPs) are known to be bactericidal and also cytotoxic to mammalian cells. Herein, we investigate the molecular mechanism of Ag NP mediated cytotoxicity in both cancer and non-cancer cells and find that optimum particle concentration leads to programmed cell death in vitro. Also, the benefit of the cytotoxic effects of Ag NPs was tested for therapeutic use in conjunction with conventional gene therapy. The synergistic effect of Ag NPs on the uracil phosphoribosyltransferase expression system sensitized the cells more towards treatment with the drug 5-fluorouracil. Induction of the apoptotic pathway makes Ag NPs a representative of a new chemosensitization strategy for future application in gene therapy

  5. Hair regrowth in alopecia areata patients following Stem Cell Educator therapy.

    Science.gov (United States)

    Li, Yanjia; Yan, Baoyong; Wang, Hepeng; Li, Heng; Li, Quanhai; Zhao, Dong; Chen, Yana; Zhang, Ye; Li, Wenxia; Zhang, Jun; Wang, Shanfeng; Shen, Jie; Li, Yunxiang; Guindi, Edward; Zhao, Yong

    2015-04-20

    Alopecia areata (AA) is one of the most common autoimmune diseases and targets the hair follicles, with high impact on the quality of life and self-esteem of patients due to hair loss. Clinical management and outcomes are challenged by current limited immunosuppressive and immunomodulating regimens. We have developed a Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, allows the cells to briefly interact with adherent human cord blood-derived multipotent stem cells (CB-SC), and returns the "educated" autologous cells to the patient's circulation. In an open-label, phase 1/phase 2 study, patients (N = 9) with severe AA received one treatment with the Stem Cell Educator therapy. The median age was 20 years (median alopecic duration, 5 years). Clinical data demonstrated that patients with severe AA achieved improved hair regrowth and quality of life after receiving Stem Cell Educator therapy. Flow cytometry revealed the up-regulation of Th2 cytokines and restoration of balancing Th1/Th2/Th3 cytokine production in the peripheral blood of AA subjects. Immunohistochemistry indicated the formation of a "ring of transforming growth factor beta 1 (TGF-β1)" around the hair follicles, leading to the restoration of immune privilege of hair follicles and the protection of newly generated hair follicles against autoimmune destruction. Mechanistic studies revealed that co-culture with CB-SC may up-regulate the expression of coinhibitory molecules B and T lymphocyte attenuator (BTLA) and programmed death-1 receptor (PD-1) on CD8β(+)NKG2D(+) effector T cells and suppress their proliferation via herpesvirus entry mediator (HVEM) ligands and programmed death-1 ligand (PD-L1) on CB-SCs. Current clinical data demonstrated the safety and efficacy of the Stem Cell Educator therapy for the treatment of AA. This innovative approach produced lasting improvement in hair regrowth in

  6. Age-old wisdom concerning cell-based therapies with added knowledge in the stem cell era: our perspectives

    Directory of Open Access Journals (Sweden)

    Preethy S

    2013-04-01

    Full Text Available Senthilkumar Preethy,1,2 Sudhakar John,1 Jegatheesan Saravana Ganesh,1 Thangavelu Srinivasan,1 Hiroshi Terunuma,3 Masaru Iwasaki,4 Samuel J Abraham1,4 1Nichi-In Centre for Regenerative Medicine, 2Hope Foundation Trust, Chennai, India; 3Biotherapy Institute of Japan, Tokyo, 4Yamanashi University School of Medicine, Chuo, Japan Abstract: Among the various strategies providing a cure for illness, cell-based therapies have caught the attention of the world with the advent of the "stem cell" era. Our inherent understanding indicates that stem cells have been in existence since the birth of multicellular organisms. However, the formal discovery of stem cells in the last century, followed by their intricate and extensive analysis, has led to clinical and translational efforts with the aim of using them in the treatment of conditions which don't have a definitive therapeutic strategy, has fueled our interest and expectations. Technological advances in our ability to study their cellular components in depth, along with surface markers and other finer constituents, that were unknown until last century, have improved our understanding, leading to several novel applications. This has created a need to establish guidelines, and in that process, there are expressed understandings and views which describe cell therapy along lines similar to that of biologic products, drugs, and devices. However, the age-old wisdom of using cells as tools for curing illness should not be misled by recent knowledge, to make cell therapy using highly complex stem cells equal to factory-synthesized and reproducible chemical compounds, drugs, or devices. This article analyses the differences between these two entities from various perspectives. Keywords: cell transplantation, drugs, regenerative medicine, stem cells

  7. Concise Review: Bone Marrow Mononuclear Cells for the Treatment of Ischemic Syndromes: Medicinal Product or Cell Transplantation?

    Science.gov (United States)

    Rico, Laura; Herrera, Concha

    2012-01-01

    In November of 2011, the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) published two scientific recommendations regarding the classification of autologous bone marrow-derived mononuclear cells (BM-MNCs) and autologous bone marrow-derived CD133+ cells as advanced therapy medicinal products (ATMPs), specifically tissue-engineered products, when intended for regeneration in ischemic heart tissue on the basis that they are not used for the same essential function (hematological restoration) that they fulfill in the donor. In vitro and in vivo evidence demonstrates that bone marrow cells are physiologically involved in adult neovascularization and tissue repair, making their therapeutic use for these purposes a simple exploitation of their own essential functions. Therefore, from a scientific/legal point of view, nonsubstantially manipulated BM-MNCs and CD133+ cells are not an ATMP, because they have a physiological role in the processes of postnatal neovascularization and, when used therapeutically for vascular restoration in ischemic tissues, they are carrying out one of their essential physiological functions (the legal definition recognizes that cells can have several essential functions). The consequences of classifying BM-MNCs and CD133+ cells as medicinal products instead of cellular transplantation, like bone marrow transplantation, in terms of costs and time for these products to be introduced into clinical practice, make this an issue of crucial importance. Therefore, the recommendations of EMA/CAT could be reviewed in collaboration with scientific societies, in light of organizational and economic consequences as well as scientific knowledge recently acquired about the mechanisms of postnatal neovascularization and the function of bone marrow in the regeneration of remote tissues. PMID:23197819

  8. Changes in T-cell subsets after radiation therapy

    International Nuclear Information System (INIS)

    Yang, S.J.; Rafla, S.; Youssef, E.; Selim, H.; Salloum, N.; Chuang, J.Y.

    1988-01-01

    The T-cell subsets of 129 patients with cancer were counted before and after radiation therapy. The cells were labeled with monoclonal antibodies that were specific for each type of T cell. Significant changes after therapy were decreases in the proportion of T-helper/inducer cells, pan-T cells, and in the ratio of T-helper/inducer to T-suppressor/cytotoxic cells. There was an increase in the percentage of T-suppressor/cytotoxic cells. When the site of the primary cancer was considered, genitourinary cancer and cancer of the head and neck both showed a decreased percentage of T-helper/inducer cells and a reduced ratio of T-helper/inducer to T-suppressor/cytotoxic cells. The percentage of pan-T cells in head and neck cancer and the ratio of T-helper/inducer to T-suppressor/cytotoxic cells in breast cancer were decreased. The percentage of T-helper cells was particularly decreased by radiation therapy in advanced stages of cancer, in higher grade tumors, and in larger tumors. The absolute numbers of various T-cell subsets were decreased in all groups

  9. Adoptive T cell therapy: Addressing challenges in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Yee Cassian

    2005-04-01

    Full Text Available Abstract Adoptive T cell therapy involves the ex vivo selection and expansion of effector cells for the treatment of patients with cancer. In this review, the advantages and limitations of using antigen-specific T cells are discussed in counterpoint to vaccine strategies. Although vaccination strategies represent more readily available reagents, adoptive T cell therapy provides highly selected T cells of defined phenotype, specificity and function that may influence their biological behavior in vivo. Adoptive T cell therapy offers not only translational opportunities but also a means to address fundamental issues in the evolving field of cancer immunotherapy.

  10. Methods for Stem Cell Production and Therapy

    Science.gov (United States)

    Valluri, Jagan V. (Inventor); Claudio, Pier Paolo (Inventor)

    2015-01-01

    The present invention relates to methods for rapidly expanding a stem cell population with or without culture supplements in simulated microgravity conditions. The present invention relates to methods for rapidly increasing the life span of stem cell populations without culture supplements in simulated microgravity conditions. The present invention also relates to methods for increasing the sensitivity of cancer stem cells to chemotherapeutic agents by culturing the cancer stem cells under microgravity conditions and in the presence of omega-3 fatty acids. The methods of the present invention can also be used to proliferate cancer cells by culturing them in the presence of omega-3 fatty acids. The present invention also relates to methods for testing the sensitivity of cancer cells and cancer stem cells to chemotherapeutic agents by culturing the cancer cells and cancer stem cells under microgravity conditions. The methods of the present invention can also be used to produce tissue for use in transplantation by culturing stem cells or cancer stem cells under microgravity conditions. The methods of the present invention can also be used to produce cellular factors and growth factors by culturing stem cells or cancer stem cells under microgravity conditions. The methods of the present invention can also be used to produce cellular factors and growth factors to promote differentiation of cancer stem cells under microgravity conditions.

  11. Stem cell and gene therapies for diabetes mellitus.

    Science.gov (United States)

    Calne, Roy Y; Gan, Shu Uin; Lee, Kok Onn

    2010-03-01

    In this Perspectives article, we comment on the progress in experimental stem cell and gene therapies that might one day become a clinical reality for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Finally, gene therapy shows some promise for the generation of insulin-producing cells. Here, we discuss two of the most frequently used approaches: in vitro gene delivery into cells which are then transplanted into the recipient and direct delivery of genes in vivo.

  12. Erythroid cells in vitro: from developmental biology to blood transfusion products.

    Science.gov (United States)

    Migliaccio, Anna Rita; Whitsett, Carolyn; Migliaccio, Giovanni

    2009-07-01

    Red blood cells (RBCs) transfusion plays a critical role in numerous therapies. Disruption of blood collection by political unrest, natural disasters and emerging infections and implementation of restrictions on the use of erythropoiesis-stimulating agents in cancer may impact blood availability in the near future. These considerations highlight the importance of developing alternative blood products. Knowledge about the processes that control RBC production has been applied to the establishment of culture conditions allowing ex-vivo generation of RBCs in numbers close to those (2.5 x 10 cells/ml) present in a transfusion, from cord blood, donated blood units or embryonic stem cells. In addition, experimental studies demonstrate that such cells protect mice from lethal bleeding. Therefore, erythroid cells generated ex vivo may be suitable for transfusion provided they can be produced safely in adequate numbers. However, much remains to be done to translate a theoretical production of approximately 2.5 x 10 RBCs in the laboratory into a 'clinical grade production process'. This review summarizes the state-of-the-art in establishing ex-vivo culture conditions for erythroid cells and discusses the most compelling issues to be addressed to translate this progress into a clinical grade transfusion product.

  13. Stem cell therapy to treat heart ischaemia

    DEFF Research Database (Denmark)

    Ali Qayyum, Abbas; Mathiasen, Anders Bruun; Kastrup, Jens

    2014-01-01

    (CABG), morbidity and mortality is still high in patients with CAD. Along with PCI and CABG or in patients without options for revascularization, stem cell regenerative therapy in controlled trials is a possibility. Stem cells are believed to exert their actions by angiogenesis and regeneration...... of cardiomyocytes. Recently published clinical trials and meta-analysis of stem cell studies have shown encouraging results with increased left ventricle ejection fraction and reduced symptoms in patients with CAD and heart failure. There is some evidence of mesenchymal stem cell being more effective compared...... to other cell types and cell therapy may be more effective in patients with known diabetes mellitus. However, further investigations are warranted....

  14. Progress toward cell-directed therapy for phenylketonuria

    Science.gov (United States)

    Harding, CO

    2009-01-01

    Phenylketonuria (PKU) is one of the most common inborn errors of metabolism with an annual incidence of approximately 1:16,000 live births in North America. Contemporary therapy relies upon lifelong dietary protein restriction and supplementation with phenylalanine-free medical foods. This therapy is expensive and unpalatable; dietary compliance is difficult to maintain throughout life. Non-adherence to the diet is associated with learning disabilities, adult-onset neurodegenerative disease, and maternal PKU syndrome. The fervent dream of many individuals with PKU is a more permanent cure for this disease. This paper will review ongoing efforts to develop viable cell-directed therapies, in particular cell transplantation and gene therapy, for the treatment of PKU. PMID:18498375

  15. Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis

    Science.gov (United States)

    2015-11-01

    1 AD_________________ Award Number: W81XWH-11-1-0593 TITLE: Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis PRINCIPAL...3. DATES COVERED (From - To) 09/15/2011 - 08/14/2015 4. TITLE AND SUBTITLE Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis 5a...4 Title of the Grant: Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis Award number: W81XWH-11-1-0593 Principal Investigator

  16. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    Shan Liu

    2016-06-01

    Full Text Available Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous. The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells, early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium, using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration, timing for cell therapy (immediate vs. a few days after injury, single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.

  17. Selection of Shared and Neoantigen-Reactive T Cells for Adoptive Cell Therapy Based on CD137 Separation

    Directory of Open Access Journals (Sweden)

    Sivan Seliktar-Ofir

    2017-10-01

    Full Text Available Adoptive cell therapy (ACT of autologous tumor infiltrating lymphocytes (TIL is an effective immunotherapy for patients with solid tumors, yielding objective response rates of around 40% in refractory patients with metastatic melanoma. Most clinical centers utilize bulk, randomly isolated TIL from the tumor tissue for ex vivo expansion and infusion. Only a minor fraction of the administered T cells recognizes tumor antigens, such as shared and mutation-derived neoantigens, and consequently eliminates the tumor. Thus, there are many ongoing effects to identify and select tumor-specific TIL for therapy; however, those approaches are very costly and require months, which is unreasonable for most metastatic patients. CD137 (4-1BB has been identified as a co-stimulatory marker, which is induced upon the specific interaction of T cells with their target cell. Therefore, CD137 can be a useful biomarker and an important tool for the selection of tumor-reactive T cells. Here, we developed and validated a simple and time efficient method for the selection of CD137-expressing T cells for therapy based on magnetic bead separation. CD137 selection was performed with clinical grade compliant reagents, and TIL were expanded in a large-scale manner to meet cell numbers required for the patient setting in a GMP facility. For the first time, the methodology was designed to comply with both clinical needs and limitations, and its feasibility was assessed. CD137-selected TIL demonstrated significantly increased antitumor reactivity and were enriched for T cells recognizing neoantigens as well as shared tumor antigens. CD137-based selection enabled the enrichment of tumor-reactive T cells without the necessity of knowing the epitope specificity or the antigen type. The direct implementation of the CD137 separation method to the cell production of TIL may provide a simple way to improve the clinical efficiency of TIL ACT.

  18. Near-infrared emitting fluorescent nanocrystals-labeled natural killer cells as a platform technology for the optical imaging of immunotherapeutic cells-based cancer therapy

    International Nuclear Information System (INIS)

    Lim, Yong Taik; Cho, Mi Young; Noh, Young-Woock; Chung, Bong Hyun; Chung, Jin Woong

    2009-01-01

    This study describes the development of near-infrared optical imaging technology for the monitoring of immunotherapeutic cell-based cancer therapy using natural killer (NK) cells labeled with fluorescent nanocrystals. Although NK cell-based immunotherapeutic strategies have drawn interest as potent preclinical or clinical methods of cancer therapy, there are few reports documenting the molecular imaging of NK cell-based cancer therapy, primarily due to the difficulty of labeling of NK cells with imaging probes. Human natural killer cells (NK92MI) were labeled with anti-human CD56 antibody-coated quantum dots (QD705) for fluorescence imaging. FACS analysis showed that the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 have no effect on the cell viability. The effect of anti-human CD56 antibody-coated QD705 labeling on the NK92MI cell function was investigated by measuring interferon gamma (IFN- γ) production and cytolytic activity. Finally, the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 showed a therapeutic effect similar to that of unlabeled NK92MI cells. Images of intratumorally injected NK92MI cells labeled with anti-human CD56 antibody-coated could be acquired using near-infrared optical imaging both in vivo and in vitro. This result demonstrates that the immunotherapeutic cells labeled with fluorescent nanocrystals can be a versatile platform for the effective tracking of injected therapeutic cells using optical imaging technology, which is very important in cell-based cancer therapies.

  19. Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy

    Directory of Open Access Journals (Sweden)

    Xinxin Han

    2017-01-01

    Full Text Available Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.

  20. Nanotechnology and stem cell therapy for cardiovascular diseases: potential applications.

    Science.gov (United States)

    La Francesca, Saverio

    2012-01-01

    The use of stem cell therapy for the treatment of cardiovascular diseases has generated significant interest in recent years. Limitations to the clinical application of this therapy center on issues of stem cell delivery, engraftment, and fate. Nanotechnology-based cell labeling and imaging techniques facilitate stem cell tracking and engraftment studies. Nanotechnology also brings exciting new opportunities to translational stem cell research as it enables the controlled engineering of nanoparticles and nanomaterials that can properly relate to the physical scale of cell-cell and cell-niche interactions. This review summarizes the most relevant potential applications of nanoscale technologies to the field of stem cell therapy for the treatment of cardiovascular diseases.

  1. FDA Warns About Stem Cell Therapies

    Science.gov (United States)

    ... Home For Consumers Consumer Updates FDA Warns About Stem Cell Therapies Share Tweet Linkedin Pin it More sharing ... see the boxed section below for more advice. Stem Cell Uses and FDA Regulation The FDA has the ...

  2. B16F1 melanoma cells upregulate melanin synthesis after photodynamic therapy

    International Nuclear Information System (INIS)

    Moder, A.; Gassner, F.; Krammer, B.; Thalhamer, J.; Hammerl, P.

    2003-01-01

    Full text: The success of photodynamic therapy (PDT) of melanotic tumors is severely limited by insufficient penetration of light into deeper tissue layers. In this study, we analyzed the effect of PDT on the melanin production of the melanoma cell line B16F1. In vitro, these cells produce only little melanin. However, after PDT we found a dramatic elevation in intracellular melanin. Melanin production increased with, both, the concentration of the sensitizing agent and the light dose, and was found to continue for several hours after cell death. PDT-induced melanin synthesis was not prevented by the addition of cycloheximide or actinomycin D prior to irradiation, indicating that de-novo protein synthesis and transcriptional activity are not required for this effect. We also analyzed tyrosinase activity, a key enzyme in melanin biosynthesis, in PDT-treated B16 cells. Tyrosinase activity was found in PDT-treated as well as untreated cells. Cell fractionation experiments showed that tyrosinase was present in the cytosolic as well as the melanosomal fractions of, both, PDT-treated (melanin-high) as well as untreated (melanin-low) cells. These data indicate that PDT-induced production of melanin is not controlled at the transcriptional or translational level and that tyrosinase is not likely an essential regulator in this process. (author)

  3. Targeting therapy-resistant cancer stem cells by hyperthermia

    DEFF Research Database (Denmark)

    Oei, A L; Vriend, L E M; Krawczyk, P M

    2017-01-01

    Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells...... are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising...

  4. Stem cell therapy for the systemic right ventricle.

    Science.gov (United States)

    Si, Ming-Sing; Ohye, Richard G

    2017-11-01

    In specific forms of congenital heart defects and pulmonary hypertension, the right ventricle (RV) is exposed to systemic levels of pressure overload. The RV is prone to failure in these patients because of its vulnerability to chronic pressure overload. As patients with a systemic RV reach adulthood, an emerging epidemic of RV failure has become evident. Medical therapies proven for LV failure are ineffective in treating RV failure. Areas covered: In this review, the pathophysiology of the failing RV under pressure overload is discussed, with specific emphasis on the pivotal roles of angiogenesis and oxidative stress. Studies investigating the ability of stem cell therapy to improve angiogenesis and mitigate oxidative stress in the setting of pressure overload are then reviewed. Finally, clinical trials utilizing stem cell therapy to prevent RV failure under pressure overload in congenital heart disease will be discussed. Expert commentary: Although considerable hurdles remain before their mainstream clinical implementation, stem cell therapy possesses revolutionary potential in the treatment of patients with failing systemic RVs who currently have very limited long-term treatment options. Rigorous clinical trials of stem cell therapy for RV failure that target well-defined mechanisms will ensure success adoption of this therapeutic strategy.

  5. The early career researcher's toolkit:translating tissue engineering, regenerative medicine and cell therapy products

    OpenAIRE

    Rafiq, Qasim A.; Ortega, Ilida; Jenkins, Stuart I.; Wilson, Samantha L.; Patel, Asha K.; Barnes, Amanda L.; Adams, Christopher F.; Delcassian, Derfogail; Smith, David

    2015-01-01

    Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in...

  6. Optimizing autologous cell grafts to improve stem cell gene therapy.

    Science.gov (United States)

    Psatha, Nikoletta; Karponi, Garyfalia; Yannaki, Evangelia

    2016-07-01

    Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically engineered hematopoietic stem cells are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels posttransplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by reduced-intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing megadoses of genetically modified CD34(+) cells into conditioned patients or by transplanting hematopoietic stem cells hematopoietic stem cells with high engrafting and repopulating potential. On the basis of the lessons gained from cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of hematopoietic stem cells for transplantation or/and their engraftability, as a platform toward the optimization of engineered stem cell grafts. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  7. Improved survival of mice bearing liver metastases of colon cancer cells treated with a combination of radioimmunotherapy and antiangiogenic therapy

    International Nuclear Information System (INIS)

    Kinuya, Seigo; Yokoyama, Kunihiko; Bai, Jingming; Michigishi, Takatoshi; Tonami, Norihisa; Koshida, Kiyoshi; Mori, Hirofumi; Shiba, Kazuhiro; Watanabe, Naoto; Shuke, Noriyuki

    2004-01-01

    We attempted to determine whether the combined regimen of radioimmunotherapy (RIT) and antiangiogenic therapy would favorably affect the survival of animals bearing liver metastases of colon cancer cells. Daily antiangiogenic therapy with 2-methoxyestradiol (2-ME), 75 mg/kg, was initiated at 3 days following intrasplenic cell inoculation of LS180 colon cancer cells. RIT with 7 MBq of 131 I-A7, an IgG1 anti-colorectal monoclonal antibody, or 131 I-HPMS-1, an irrelevant IgG1, was conducted at 7 days. Production of vascular endothelial growth factor (VEGF) by LS180 cells was assessed in vitro. All nontreated mice died by 31 days following cell inoculation (n=5). Monotherapy comprising 2-ME treatment resulted in slightly better survival of mice (n=8) (P 131 I-A7 RIT displayed a marked therapeutic effect (n=8) (P 131 I-A7 RIT and antiangiogenic therapy demonstrated a superior therapeutic effect in comparison to monotherapy consisting of either RIT or antiangiogenic therapy (n=10) (P 131 I-HPMS-1 RIT failed to provide an appreciable benefit (n=5). Treatment with 2-ME decreased VEGF production by LS180 cells in a dose-dependent fashion. In conclusion, a combination regimen comprising RIT and antiangiogenic therapy initiated at the early stage of metastasis would be of great benefit in terms of improvement of the therapeutic efficacy with respect to liver metastases. (orig.)

  8. Endogenous T-Cell Therapy: Clinical Experience.

    Science.gov (United States)

    Yee, Cassian; Lizee, Greg; Schueneman, Aaron J

    2015-01-01

    Adoptive cellular therapy represents a robust means of augmenting the tumor-reactive effector population in patients with cancer by adoptive transfer of ex vivo expanded T cells. Three approaches have been developed to achieve this goal: the use of tumor-infiltrating lymphocytes or tumor-infiltrating lymphocytess extracted from patient biopsy material; the redirected engineering of lymphocytes using vectors expressing a chimeric antigen receptor and T-cell receptor; and third, the isolation and expansion of often low-frequency endogenous T cells (ETCs) reactive to tumor antigens from the peripheral blood of patients. This last form of adoptive transfer of T cells, known as ETC therapy, requires specialized methods to isolate and expand from peripheral blood the very low-frequency tumor-reactive T cells, methods that have been developed over the last 2 decades, to the point where such an approach may be broadly applicable not only for the treatment of melanoma but also for that of other solid tumor malignancies. One compelling feature of ETC is the ability to rapidly deploy clinical trials following identification of a tumor-associated target epitope, a feature that may be exploited to develop personalized antigen-specific T-cell therapy for patients with almost any solid tumor. With a well-validated antigen discovery pipeline in place, clinical studies combining ETC with agents that modulate the immune microenvironment can be developed that will transform ETC into a feasible treatment modality.

  9. Cell cycle kinetics and radiation therapy

    International Nuclear Information System (INIS)

    Mendelsohn, M.L.

    1975-01-01

    Radiation therapy as currently practiced involves the subtle largely empirical art of balancing the recurrence of cancer due to undertreatment against severe damage to local tissues due to overtreatment. Therapeutic results too often fall short of desired success rates; yet, the therapist is continually tantalized to the likelihood that a slight shift of therapeutic ratio favoring normal tissue over cancer would have a profoundly beneficial effect. The application of cell cycle kinetics to radiation therapy is one hope for improving the therapeutic ratio; but, as I will try to show, kinetic approaches are complex, poorly understood, and presently too elusive to elicit confidence or to be used clinically. Their promise lies in their diversity and in the magnitude of our ignorance about how they work and how they should be used. Potentially useful kinetic approaches to therapy can be grouped into three classes. The first class takes advantage of intracyclic differential sensitivity, an effect involving the metabolism and biology of the cell cycle; its strategies are based on synchronization of cells over intervals of hours to days. The second class involves the distinction between cycling and noncycling cells; its strategies are based on the resistance of noncycling cells to cycle-linked radiation sensitizers and chemotherapeutic agents. The third class uses cell repopulation between fractions; its strategies are based on the relative growth rates of tumor and relevant normal tissue before and after perturbation

  10. Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites' marketing of stem cell therapies.

    Science.gov (United States)

    Murdoch, Blake; Zarzeczny, Amy; Caulfield, Timothy

    2018-02-28

    To identify the frequency and qualitative characteristics of stem cell-related marketing claims made on websites of clinics featuring common types of complementary and alternative medicine practitioners. The involvement of complementary and alternative medicine practitioners in the marketing of stem cell therapies and stem cell-related interventions is understudied. This research explores the extent to which they are involved and collaborate with medical professionals. This knowledge will help with identifying and evaluating potential policy responses to this growing market. Systematic website analysis. Global. US and English-language bias due to methodology. Representations made on clinic websites in relation to practitioner types, stem cell therapies and their targets, stem cell-related interventions. Statements about stem cell therapies relating to evidence of inefficacy, limited evidence of efficacy, general procedural risks, risks specific to the mode of therapy, regulatory status, experimental or unproven nature of therapy. Use of hype language (eg, language that exaggerates potential benefits). 243 websites offered stem cell therapies. Many websites advertised stem cell transplantation from multiple sources, such as adipose-derived (112), bone marrow-derived (100), blood-derived (28), umbilical cord-derived (26) and others. Plant stem cell-based treatments and products (20) were also advertised. Purposes for and targets of treatment included pain, physical injury, a wide range of diseases and illnesses, cosmetic concerns, non-cosmetic ageing, sexual enhancement and others. Medical doctors (130), chiropractors (53) and naturopaths (44) commonly work in the clinics we found to be offering stem cell therapies. Few clinic websites advertising stem cell therapies included important additional information, including statements about evidence of inefficacy (present on only 12.76% of websites), statements about limited evidence of efficacy (18.93%), statements of

  11. A novel in vitro method for detecting undifferentiated human pluripotent stem cells as impurities in cell therapy products using a highly efficient culture system.

    Directory of Open Access Journals (Sweden)

    Keiko Tano

    Full Text Available Innovative applications of cell therapy products (CTPs derived from human pluripotent stem cells (hPSCs in regenerative medicine are currently being developed. The presence of residual undifferentiated hPSCs in CTPs is a quality concern associated with tumorigencity. However, no simple in vitro method for direct detection of undifferentiated hPSCs that contaminate CTPs has been developed. Here, we show a novel approach for direct and sensitive detection of a trace amount of undifferentiated human induced pluripotent stem cells (hiPSCs using a highly efficient amplification method in combination with laminin-521 and Essential 8 medium. Essential 8 medium better facilitated the growth of hiPSCs dissociated into single cells on laminin-521 than in mTeSR1 medium. hiPSCs cultured on laminin-521 in Essential 8 medium were maintained in an undifferentiated state and they maintained the ability to differentiate into various cell types. Essential 8 medium allowed robust hiPSC proliferation plated on laminin-521 at low cell density, whereas mTeSR1 did not enhance the cell growth. The highly efficient culture system using laminin-521 and Essential 8 medium detected hiPSCs spiked into primary human mesenchymal stem cells (hMSCs or human neurons at the ratio of 0.001%-0.01% as formed colonies. Moreover, this assay method was demonstrated to detect residual undifferentiated hiPSCs in cell preparations during the process of hMSC differentiation from hiPSCs. These results indicate that our highly efficient amplification system using a combination of laminin-521 and Essential 8 medium is able to detect a trace amount of undifferentiated hPSCs contained as impurities in CTPs and would contribute to quality assessment of hPSC-derived CTPs during the manufacturing process.

  12. Stem Cells for Cardiac Regeneration by Cell Therapy and Myocardial Tissue Engineering

    Science.gov (United States)

    Wu, Jun; Zeng, Faquan; Weisel, Richard D.; Li, Ren-Ke

    Congestive heart failure, which often occurs progressively following a myocardial infarction, is characterized by impaired myocardial perfusion, ventricular dilatation, and cardiac dysfunction. Novel treatments are required to reverse these effects - especially in older patients whose endogenous regenerative responses to currently available therapies are limited by age. This review explores the current state of research for two related approaches to cardiac regeneration: cell therapy and tissue engineering. First, to evaluate cell therapy, we review the effectiveness of various cell types for their ability to limit ventricular dilatation and promote functional recovery following implantation into a damaged heart. Next, to assess tissue engineering, we discuss the characteristics of several biomaterials for their potential to physically support the infarcted myocardium and promote implanted cell survival following cardiac injury. Finally, looking ahead, we present recent findings suggesting that hybrid constructs combining a biomaterial with stem and supporting cells may be the most effective approaches to cardiac regeneration.

  13. Stem Cell Therapy to Improve Burn Wound Healing

    Science.gov (United States)

    2017-03-01

    Award Number: W81XWH-13-2-0024 TITLE: Stem Cell Therapy to Improve Burn Wound Healing PRINCIPAL INVESTIGATOR: Carl Schulman, MD, PhD, MSPH...NUMBER Stem Cell Therapy to Improve Burn Wound Healing 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Carl Schulman, MD, PhD, MSPH...treatments, steroid injections, and compression garments. Mesenchymal stem cells (MSC’s) have been used in a variety of clinical applications to repair

  14. Stem Cell Therapies in Orthopaedic Trauma

    OpenAIRE

    Marcucio, Ralph S.; Nauth, Aaron; Giannoudis, Peter V.; Bahney, Chelsea; Piuzzi, Nicolas S.; Muschler, George; Miclau, Theodore

    2015-01-01

    Stem cells offer great promise to help understand the normal mechanisms of tissue renewal, regeneration, and repair, and also for development of cell-based therapies to treat patients after tissue injury. Most adult tissues contain stem cells and progenitor cells that contribute to homeostasis, remodeling and repair. Multiple stem and progenitor cell populations in bone are found in the marrow, the endosteum, and the periosteum. They contribute to the fracture healing process after injury and...

  15. Basal cell carcinoma after radiation therapy

    International Nuclear Information System (INIS)

    Shimbo, Keisuke; Terashi, Hiroto; Ishida, Yasuhisa; Tahara, Shinya; Osaki, Takeo; Nomura, Tadashi; Ejiri, Hirotaka

    2008-01-01

    We reported two cases of basal cell carcinoma (BCC) that developed after radiation therapy. A 50-year-old woman, who had received an unknown amount of radiation therapy for the treatment of intracranial germinoma at the age of 22, presented with several tumors around the radiation ulcer. All tumors showed BCC. A 33-year-old woman, who had received an unknown amount of radiation therapy on the head for the treatment of leukemia at the age of 2, presented with a black nodule within the area of irradiation. The tumor showed BCC. We discuss the occurrence of BCC after radiation therapy. (author)

  16. Chimeric Antigen Receptor T Cell (Car T Cell Therapy In Hematology

    Directory of Open Access Journals (Sweden)

    Pinar Ataca

    2015-12-01

    Full Text Available It is well demonstrated that immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation (HSCT. Adoptive T cell transfer has been improved to be more specific and potent and cause less off-target toxicities. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR and chimeric antigen receptor (CAR modified T cells. On July 1, 2014, the United States Food and Drug Administration granted ‘breakthrough therapy’ designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the beneficiaries of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical-clinical studies, effectiveness and drawbacks of this strategy.

  17. Cell therapy in femur fractures

    International Nuclear Information System (INIS)

    Gonzalez Gonzalez, Jorge Arturo; Gamez Perez, Anadely; Rodriguez Orta, Celia

    2012-01-01

    Regenerative medicine has opened another opportunity for effective consolidation and rapid recovery of patients with traumatic injuries. We present a 46 year-old white male patient with a history of traffic accident. A middle third left femur fracture was diagnosed and plain radiographs showed IV grade comminution. He was released after 20 days of hospitalization with persistent pain despite of pain medication every 4-6 hours. Cell therapy was prescribed and it was performed on outpatient basis. After 48 hours the improvement was increased progressively, stability was achieved and pain disappeared in the fracture site, this was a symptom present since the accident. 8 weeks after cell therapy, radiological improvement was observed. In general, his evolution was considered satisfactory for the fast recovery and its incorporation into social life. This is the first patient in Artemisa province who underwent this new type of therapy and as far as we know at the time of this writing, it is also the first reported in the scientific literature in Cuba

  18. Advanced Therapy Medicinal Products (ATMPand exemptions to the Regulation 1394/2007: how confident can we be? An exploratory analysis.

    Directory of Open Access Journals (Sweden)

    Philippe eVan Wilder

    2012-02-01

    Full Text Available The market authorisation procedure for medicinal products for human use is relying on their demonstrated efficacy, safety and pharmaceutical quality. This applies to all medicinal products whether of chemical or biological origin. Since October 2009, the first advanced therapy medicinal product (ATMP has been authorised through the centralized procedure. ATMPs are gene therapy medicinal products, somatic cell therapy medicinal products or tissue-engineered products.An appropriate ATMP- Regulation is dealing with ATMP requirements.Two exemptions are foreseen to the ATMP-Regulation: a. Products, which were legally on the Community market when the Regulation became applicable, should comply to the Regulation by 30 December 2012. b.the hospital exemption rule for non routine products for an individual patient. In this work we explored whether the actual application of the Regulation on ATMPs is in line with the aim of the Regulation in terms of guaranteeing the highest level of health protection for patients. Based on the analysis of the relative efficacy of the only EC authorized ATMP and its exempted alternatives, there is evidence against this Regulation 1394/2007 assumption.

  19. Advanced Therapy Medicinal Products and Exemptions to the Regulation 1394/2007: How Confident Can We be? An Exploratory Analysis.

    Science.gov (United States)

    Van Wilder, Philippe

    2012-01-01

    The market authorization procedure for medicinal products for human use is relying on their demonstrated efficacy, safety, and pharmaceutical quality. This applies to all medicinal products whether of chemical or biological origin. Since October 2009, the first advanced therapy medicinal product (ATMP) has been authorized through the centralized procedure. ATMPs are gene therapy medicinal products, somatic cell therapy medicinal products or tissue-engineered products. An appropriate ATMP - Regulation is dealing with ATMP requirements. Two exemptions are foreseen to the ATMP Regulation: (a) Products, which were legally on the Community market when the Regulation became applicable, should comply to the Regulation by December 30, 2012. (b) The hospital exemption rule for non-routine products for an individual patient. In this work we explored whether the actual application of the Regulation on ATMPs is in line with the aim of the Regulation in terms of guaranteeing the highest level of health protection for patients. Based on the analysis of the relative efficacy of the only EC authorized ATMP and its exempted alternatives, there is evidence against this Regulation 1394/2007 assumption.

  20. Stem Cell Therapies in Retinal Disorders

    Directory of Open Access Journals (Sweden)

    Aakriti Garg

    2017-02-01

    Full Text Available Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. While human embryonic stem cells (ESCs have provided the precedent for regenerative medicine, the development of induced pluripotent stem cells (iPSCs revolutionized this field. iPSCs allow for the development of many types of retinal cells, including those of the retinal pigment epithelium, photoreceptors, and ganglion cells, and can model polygenic diseases such as age-related macular degeneration. Cellular programming and reprogramming technology is especially useful in retinal diseases, as it allows for the study of living cells that have genetic variants that are specific to patients’ diseases. Since iPSCs are a self-renewing resource, scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Challenges in the use of stem cells are present from the scientific, ethical, and political realms. These include transplant complications leading to anatomically incorrect placement, concern for tumorigenesis, and incomplete targeting of differentiation leading to contamination by different types of cells. Despite these limitations, human ESCs and iPSCs specific to individual patients can revolutionize the study of retinal disease and may be effective therapies for conditions currently considered incurable.

  1. Stem Cell Therapy: A Promising Therapeutic Method for Intracerebral Hemorrhage.

    Science.gov (United States)

    Gao, Liansheng; Xu, Weilin; Li, Tao; Chen, Jingyin; Shao, Anwen; Yan, Feng; Chen, Gao

    2018-01-01

    Spontaneous intracerebral hemorrhage (ICH) is one type of the most devastating cerebrovascular diseases worldwide, which causes high morbidity and mortality. However, efficient treatment is still lacking. Stem cell therapy has shown good neuroprotective and neurorestorative effect in ICH and is a promising treatment. In this study, our aim was to review the therapeutic effects, strategies, related mechanisms and safety issues of various types of stem cell for ICH treatment. Numerous studies had demonstrated the therapeutic effects of diverse stem cell types in ICH. The potential mechanisms include tissue repair and replacement, neurotrophy, promotion of neurogenesis and angiogenesis, anti-apoptosis, immunoregulation and anti-inflammation and so forth. The microenvironment of the central nervous system (CNS) can also influence the effects of stem cell therapy. The detailed therapeutic strategies for ICH treatment such as cell type, the number of cells, time window, and the routes of medication delivery, varied greatly among different studies and had not been determined. Moreover, the safety issues of stem cell therapy for ICH should not be ignored. Stem cell therapy showed good therapeutic effect in ICH, making it a promising treatment. However, safety should be carefully evaluated, and more clinical trials are required before stem cell therapy can be extensively applied to clinical use.

  2. Pituitary cell differentiation from stem cells and other cells: toward restorative therapy for hypopituitarism?

    Science.gov (United States)

    Willems, Christophe; Vankelecom, Hugo

    2014-01-01

    The pituitary gland, key regulator of our endocrine system, produces multiple hormones that steer essential physiological processes. Hence, deficient pituitary function (hypopituitarism) leads to severe disorders. Hypopituitarism can be caused by defective embryonic development, or by damage through tumor growth/resection and traumatic brain injury. Lifelong hormone replacement is needed but associated with significant side effects. It would be more desirable to restore pituitary tissue and function. Recently, we showed that the adult (mouse) pituitary holds regenerative capacity in which local stem cells are involved. Repair of deficient pituitary may therefore be achieved by activating these resident stem cells. Alternatively, pituitary dysfunction may be mended by cell (replacement) therapy. The hormonal cells to be transplanted could be obtained by (trans-)differentiating various kinds of stem cells or other cells. Here, we summarize the studies on pituitary cell regeneration and on (trans-)differentiation toward hormonal cells, and speculate on restorative therapies for pituitary deficiency.

  3. Temporary corneal stem cell dysfunction after radiation therapy

    International Nuclear Information System (INIS)

    Hiroshi, Fujishima; Kazuo, Tsubota

    1996-01-01

    Radiation therapy can cause corneal and conjuctival abnormalities that sometimes require surgical treatment. Corneal stem cell dysfunction is described, which recovered after the cessation of radiation. Methods - A 44-year-old man developed a corneal epithelial abnormality associated with conjuctival and corneal inflammation following radiation therapy for maxillary cancer. Examination of brush cytology samples showed goblet cells in the upper and lower parts of the cornea, which showed increased fluorescein permeability, and intraepithelial lymphocytes. Impression cytology showed goblet cells in the same part of the cornea. Specular microscopy revealed spindle type epithelial cells. Patient follow up included artificial tears and an antibiotic ophthalmic ointment. The corneal abnormalities resolved after 4 months with improved visual acuity without any surgical intervention, but the disappearance of the palisades of Vogt did not recover at 1 year after radiation. Radiation therapy in this patient caused temporary stem cell dysfunction which resulted in conjunctivalisation in a part of the cornea. Although limbal stem cell function did not fully recover, this rare case suggested that medical options should be considered before surgery. (Author)

  4. Marketing Regulatory Oversight of Advanced Therapy Medicinal Products (ATMPs) in Europe: The EMA/CAT Perspective.

    Science.gov (United States)

    Salmikangas, Paula; Schuessler-Lenz, Martina; Ruiz, Sol; Celis, Patrick; Reischl, Ilona; Menezes-Ferreira, Margarida; Flory, Egbert; Renner, Matthias; Ferry, Nicolas

    2015-01-01

    With the release of Regulation 1394/2007, a new framework for gene and cell therapy medicinal products and tissue-engineered products was established in the European Union. For all three product classes, called advanced therapy medicinal products, a centralised marketing authorisation became mandatory. The European Medicines Agency (EMA) together with its Committee for Advanced Therapies, Committee for Human Medicinal Products and the network of national agencies is responsible for scientific evaluation of the marketing authorisation applications. For a new application, data and information relating to manufacturing processes and quality control of the active substance and the final product have to be submitted for evaluation together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMPs are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines. Due to the diversity of ATMPs, a tailored approach for regulating these products is considered necessary. Thus, a risk-based approach has been introduced for ATMPs allowing flexibility for the regulatory requirements. Since the regulatory framework for ATMPs was established, five products have been licenced in the European Union. However, the pipeline of new ATMPs is much bigger, as seen from the significant numbers of different products discussed by the CAT in scientific advice and classification procedures. In 2013, a public consultation on the ATMP Regulation was conducted by the European Commission, and the results were published in 2014. The report proposes several improvements for the current framework and established procedures for the regulation of ATMPs.

  5. Good manufacturing practice-compliant expansion of marrow-derived stem and progenitor cells for cell therapy.

    Science.gov (United States)

    Gastens, Martin H; Goltry, Kristin; Prohaska, Wolfgang; Tschöpe, Diethelm; Stratmann, Bernd; Lammers, Dirk; Kirana, Stanley; Götting, Christian; Kleesiek, Knut

    2007-01-01

    Ex vivo expansion is being used to increase the number of stem and progenitor cells for autologous cell therapy. Initiation of pivotal clinical trials testing the efficacy of these cells for tissue repair has been hampered by the challenge of assuring safe and high-quality cell production. A strategy is described here for clinical-scale expansion of bone marrow (BM)-derived stem cells within a mixed cell population in a completely closed process from cell collection through postculture processing using sterile connectable devices. Human BM mononuclear cells (BMMNC) were isolated, cultured for 12 days, and washed postharvest using either standard open procedures in laminar flow hoods or using automated closed systems. Conditions for these studies were similar to long-term BM cultures in which hematopoietic and stromal components are cultured together. Expansion of marrow-derived stem and progenitor cells was then assessed. Cell yield, number of colony forming units (CFU), phenotype, stability, and multilineage differentiation capacity were compared from the single pass perfusion bioreactor and standard flask cultures. Purification of BMMNC using a closed Ficoll gradient process led to depletion of 98% erythrocytes and 87% granulocytes, compared to 100% and 70%, respectively, for manual processing. After closed system culture, mesenchymal progenitors, measured as CD105+CD166+CD14-CD45- and fibroblastic CFU, expanded 317- and 364-fold, respectively, while CD34+ hematopoietic progenitors were depleted 10-fold compared to starting BMMNC. Cultured cells exhibited multilineage differentiation by displaying adipogenic, osteogenic, and endothelial characteristics in vitro. No significant difference was observed between manual and bioreactor cultures. Automated culture and washing of the cell product resulted in 181 x 10(6) total cells that were viable and contained fibroblastic CFU for at least 24 h of storage. A combination of closed, automated technologies enabled

  6. Non-genetic engineering of cells for drug delivery and cell-based therapy.

    Science.gov (United States)

    Wang, Qun; Cheng, Hao; Peng, Haisheng; Zhou, Hao; Li, Peter Y; Langer, Robert

    2015-08-30

    Cell-based therapy is a promising modality to address many unmet medical needs. In addition to genetic engineering, material-based, biochemical, and physical science-based approaches have emerged as novel approaches to modify cells. Non-genetic engineering of cells has been applied in delivering therapeutics to tissues, homing of cells to the bone marrow or inflammatory tissues, cancer imaging, immunotherapy, and remotely controlling cellular functions. This new strategy has unique advantages in disease therapy and is complementary to existing gene-based cell engineering approaches. A better understanding of cellular systems and different engineering methods will allow us to better exploit engineered cells in biomedicine. Here, we review non-genetic cell engineering techniques and applications of engineered cells, discuss the pros and cons of different methods, and provide our perspectives on future research directions. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM).

    Science.gov (United States)

    Bader, Peter; Kuçi, Zyrafete; Bakhtiar, Shahrzad; Basu, Oliver; Bug, Gesine; Dennis, Michael; Greil, Johann; Barta, Aniko; Kállay, Krisztián M; Lang, Peter; Lucchini, Giovanna; Pol, Raj; Schulz, Ansgar; Sykora, Karl-Walter; von Luettichau, Irene; Herter-Sprie, Grit; Uddin, Mohammad Ashab; Jenkin, Phil; Alsultan, Abdulrahman; Buechner, Jochen; Stein, Jerry; Kelemen, Agnes; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Hutter, Martin; Schäfer, Richard; Seifried, Erhard; Klingebiel, Thomas; Bonig, Halvard; Kuçi, Selim

    2018-01-29

    The inability to generate mesenchymal stromal cells (MSCs) of consistent potency likely is responsible for inconsistent clinical outcomes of patients with aGvHD receiving MSC products. We developed a novel MSC manufacturing protocol characterized by high in vitro potency and near-identity of individual doses, referred to as "MSC-Frankfurt am Main (MSC-FFM)". Herein, we report outcomes of the 69 patients who have received MSC-FFM. These were 51 children and 18 adults with refractory aGvHD grade II (4%), III (36%) or IV (59%). Patients were refractory either to frontline therapy (steroids) (29%) or to steroids and 1-5 additional lines of immunosuppressants (71%) were given infusions in four weekly intervals. The day 28 overall response rate was 83%; at the last follow-up, 61% and 25% of patients were in complete or partial remission. The median follow-up was 8.1 months. Six-month estimate for cumulative incidence of non-relapse mortality was 27% (range, 16-38); leukemia relapse mortality was 2% (range, 0-5). This was associated with a superior six-month overall survival (OS) probability rate of 71% (range, 61-83), compared to the outcome of patients not treated with MSC-FFM. This novel product was effective in children and adults, suggesting that MSC-FFM represents a promising therapy for steroid refractory aGvHD.

  8. Stem Cell Therapy for Congestive Heart Failure

    Directory of Open Access Journals (Sweden)

    Gunduz E

    2011-01-01

    Full Text Available IntroductionHeart failure is a major cardiovascular health problem. Coronary artery disease is the leading cause of congestive heart failure (CHF [1]. Cardiac transplantation remains the most effective long-term treatment option, however is limited primarily by donor availability, rejection and infections. Mechanical circulatory support has its own indications and limitations [2]. Therefore, there is a need to develop more effective therapeutic strategies.Recently, regenerative medicine has received considerable scientific attention in the cardiovascular arena. We report here our experience demonstrating the beneficial effects of cardiac stem cell therapy on left ventricular functions in a patient with Hodgkin’s lymphoma (HL who developed CHF due to ischemic heart disease during the course of lymphoma treatment. Case reportA 58-year-old male with relapsed HL was referred to our bone marrow transplantation unit in October 2009. He was given 8 courses of combination chemotherapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD between June 2008 and February 2009 and achieved complete remission. However, his disease relapsed 3 months after completing the last cycle of ABVD and he was decided to be treated with DHAP (cisplatin, cytarabine, dexamethasone followed autologous stem cell transplantation (SCT. After the completion of first course of DHAP regimen, he developed acute myocardial infarction (AMI and coronary artery bypass grafting (CABG was performed. After his cardiac function stabilized, 3 additional courses of DHAP were given and he was referred to our centre for consideration of autologous SCT. Computed tomography scans obtained after chemotherapy confirmed complete remission. Stem cells were collected from peripheral blood after mobilization with 10 µg/kg/day granulocyte colony-stimulating factor (G-CSF subcutaneously. Collection was started on the fifth day of G-CSF and performed for 3 consecutive days. Flow cytometric

  9. Suicidal gene therapy with rabbit cytochrome P450 4B1/4-ipomeanol, 2-aminoanthracene system in glioma cell

    International Nuclear Information System (INIS)

    Jang, Su Jin; Kang, Joo Hyun; Kim, Kwang Il; Lee, Tae Sup; Lee, Yong Jin; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo

    2010-01-01

    Suicidal gene therapy is based on the transduction of tumor cells with 'suicide' genes encoding for prodrugactivating enzymes that render target cells susceptible to prodrug treatment. Suicidal gene therapy results in the death of tumor with the expression of gene encoding enzyme that converts non-toxic prodrug into cytotoxic product. Cytochrome P450 4B1 (CYP4B1) activates 4- ipomeanol (4-ipo) and 2-aminoanthracene (2-AA) to cytotoxic furane epoxide and unsaturated dialdehyde intermediate. In this study, therapeutic effects of suicidal gene therapy with rabbit CYP4B1/4-ipo or CYP4B1/2-AA system

  10. Advances in Bone Marrow Stem Cell Therapy for Retinal Dysfunction

    Science.gov (United States)

    Park, Susanna S.; Moisseiev, Elad; Bauer, Gerhard; Anderson, Johnathon D.; Grant, Maria B.; Zam, Azhar; Zawadzki, Robert J.; Werner, John S.; Nolta, Jan A.

    2016-01-01

    The most common cause of untreatable vision loss is dysfunction of the retina. Conditions, such as age-related macular degeneration, diabetic retinopathy and glaucoma remain leading causes of untreatable blindness worldwide. Various stem cell approaches are being explored for treatment of retinal regeneration. The rationale for using bone marrow stem cells to treat retinal dysfunction is based on preclinical evidence showing that bone marrow stem cells can rescue degenerating and ischemic retina. These stem cells have primarily paracrine trophic effects although some cells can directly incorporate into damaged tissue. Since the paracrine trophic effects can have regenerative effects on multiple cells in the retina, the use of this cell therapy is not limited to a particular retinal condition. Autologous bone marrow-derived stem cells are being explored in early clinical trials as therapy for various retinal conditions. These bone marrow stem cells include mesenchymal stem cells, mononuclear cells and CD34+ cells. Autologous therapy requires no systemic immunosuppression or donor matching. Intravitreal delivery of CD34+ cells and mononuclear cells appears to be tolerated and is being explored since some of these cells can home into the damaged retina after intravitreal administration. The safety of intravitreal delivery of mesenchymal stem cells has not been well established. This review provides an update of the current evidence in support of the use of bone marrow stem cells as treatment for retinal dysfunction. The potential limitations and complications of using certain forms of bone marrow stem cells as therapy are discussed. Future directions of research include methods to optimize the therapeutic potential of these stem cells, non-cellular alternatives using extracellular vesicles, and in vivo high-resolution retinal imaging to detect cellular changes in the retina following cell therapy. PMID:27784628

  11. Advances of reporter gene monitoring stem cell therapy

    International Nuclear Information System (INIS)

    Zhou Xiang; Yin Hongyan; Zhang Yifan

    2010-01-01

    Stem cell therapy research has made great progress, demonstrating a broad application prospects. However, stem cell therapy as a new disease treatment, there are still many problems to be solved. Reporter gene imaging is a rapid development in recent years, a non-invasive, sensitive method of monitoring of stem cells, in particular radionuclide reporter gene imaging has high sensitivity and specificity of the advantages of strong and can carry out imaging of deep tissue and repeat imaging, is a tracer in vivo conditions, the most promising stem cell transplantation technique, showing good prospects for development. (authors)

  12. Perspectives on Regulatory T Cell Therapies

    OpenAIRE

    Probst-Kepper, Michael; Kröger, Andrea; Garritsen, Henk S.P.; Buer, Jan

    2009-01-01

    Adoptive transfer in animal models clearly indicate an essential role of CD4+ CD25+ FOXP3+ regulatory T (Treg) cells in prevention and treatment of autoimmune and graft-versus-host disease. Thus, Treg cell therapies and development of drugs that specifically enhance Treg cell function and development represent promising tools to establish dominant tolerance. So far, lack of specific markers to differentiate human Treg cells from activated CD4+ CD25+ effector T cells, which also express FOXP3 ...

  13. Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

    International Nuclear Information System (INIS)

    Tsuno, Hiroaki; Yoshida, Toshiko; Nogami, Makiko; Koike, Chika; Okabe, Motonori; Noto, Zenko; Arai, Naoya; Noguchi, Makoto; Nikaido, Toshio

    2012-01-01

    Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAMα cells and induced to osteogenic status—their in vivo osteogenesis was subsequently investigated in rats. It was found that HAMα cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAMα cells. The expression of osteocalcin mRNA was increased in HAMα cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAMα cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: ► Human amniotic mesenchymal cells include cells (HAMα cells) that have the properties of MSCs. ► HAMα cells have excellent osteogenic differentiation potential. ► Osteogenic differentiation ability of HAMα was amplified by calcium phosphate scaffolds. ► HAMα cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

  14. [Classification of cell-based medicinal products and legal implications: An overview and an update].

    Science.gov (United States)

    Scherer, Jürgen; Flory, Egbert

    2015-11-01

    In general, cell-based medicinal products do not represent a uniform class of medicinal products, but instead comprise medicinal products with diverse regulatory classification as advanced-therapy medicinal products (ATMP), medicinal products (MP), tissue preparations, or blood products. Due to the legal and scientific consequences of the development and approval of MPs, classification should be clarified as early as possible. This paper describes the legal situation in Germany and highlights specific criteria and concepts for classification, with a focus on, but not limited to, ATMPs and non-ATMPs. Depending on the stage of product development and the specific application submitted to a competent authority, legally binding classification is done by the German Länder Authorities, Paul-Ehrlich-Institut, or European Medicines Agency. On request by the applicants, the Committee for Advanced Therapies may issue scientific recommendations for classification.

  15. Human Embryonic Stem Cell Therapy in Crohn's Disease: A Case Report.

    Science.gov (United States)

    Shroff, Geeta

    2016-02-29

    Crohn's disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565,000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn's disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn's disease. A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn's disease.

  16. Dynamic imaging for CAR-T-cell therapy.

    Science.gov (United States)

    Emami-Shahri, Nia; Papa, Sophie

    2016-04-15

    Chimaeric antigen receptor (CAR) therapy is entering the mainstream for the treatment of CD19(+)cancers. As is does we learn more about resistance to therapy and the role, risks and management of toxicity. In solid tumour CAR therapy research the route to the clinic is less smooth with a wealth of challenges facing translating this, potentially hugely valuable, therapeutic option for patients. As we strive to understand our successes, and navigate the challenges, having a clear understanding of how adoptively transferred CAR-T-cells behavein vivoand in human trials is invaluable. Harnessing reporter gene imaging to enable detection and tracking of small numbers of CAR-T-cells after adoptive transfer is one way by which we can accomplish this. The compatibility of certain reporter gene systems with tracers available routinely in the clinic makes this approach highly useful for future appraisal of CAR-T-cell success in humans. © 2016 Authors; published by Portland Press Limited.

  17. Rational Autologous Cell Sources For Therapy of Heart Failure - Vehicles and Targets For Gene and RNA Therapies.

    Science.gov (United States)

    Lampinen, Milla; Vento, Antti; Laurikka, Jari; Nystedt, Johanna; Mervaala, Eero; Harjula, Ari; Kankuri, Esko

    2016-01-01

    This review focuses on the possibilities for intraoperative processing and isolation of autologous cells, particularly atrial appendage-derived cells (AADCs) and cellular micrografts, and their straightforward use in cell transplantation for heart failure therapy. We review the potential of autologous tissues to serve as sources for cell therapy and consider especially those tissues that are used in surgery but from which the excess is currently discarded as surgical waste. We compare the inculture expanded cells to the freshly isolated ones in terms of evidence-based cost-efficacy and their usability as gene- and RNA therapy vehicles. We also review how financial and authority-based decisions and restrictions sculpt the landscape for patients to participate in academic-based trials. Finally, we provide an insight example into AADCs isolation and processing for epicardial therapy during coronary artery bypass surgery.

  18. Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy.

    Science.gov (United States)

    Haase, Doreen; Puan, Kia Joo; Starke, Mireille; Lai, Tuck Siong; Soh, Melissa Yan Ling; Karunanithi, Iyswariya; San Luis, Boris; Poh, Tuang Yeow; Yusof, Nurhashikin; Yeap, Chun Hsien; Phang, Chew Yen; Chye, Willis Soon Yuan; Chan, Marieta; Koh, Mickey Boon Chai; Goh, Yeow Tee; Bertin-Maghit, Sebastien; Nardin, Alessandra; Ho, Liam Pock; Rotzschke, Olaf

    2015-01-01

    Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large-scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation.

  19. Adoptive regulatory T cell therapy: challenges in clinical transplantation.

    Science.gov (United States)

    Safinia, Niloufar; Sagoo, Pervinder; Lechler, Robert; Lombardi, Giovanna

    2010-08-01

    The identification and characterisation of regulatory T cells (Tregs) has recently opened up exciting opportunities for Treg cell therapy in transplantation. In this review, we outline the basic biology of Tregs and discuss recent advances and challenges for the identification, isolation and expansion of these cells for cell therapy. Tregs of thymic origin have been shown to be key regulators of immune responses in mice and humans, preventing autoimmunity, graft-versus-host disease and organ graft rejection in the transplantation setting. To date, a variety of different methods to isolate and expand Tregs ex vivo have been advocated. Although promising, relatively few clinical trials of human Treg cell infusion have been initiated. Many key questions about Treg cell therapy still remain and here we provide an in-depth analysis and highlight the challenges and opportunities for immune intervention with Treg-based therapeutics in clinical transplantation.

  20. Cyclooxygenase inhibitors potentiate receptor tyrosine kinase therapies in bladder cancer cells in vitro

    Directory of Open Access Journals (Sweden)

    Bourn J

    2018-06-01

    -Kit receptors. RTKIs increased the expression of COX-2 in h-5637 and K9TCC#1Lillie cells. Co-treatment of indomethacin inhibited AB1010-induced COX-2 expression leading to an additive effect in inhibition of cell viability and PGE2 production in tested TCC cells.Conclusion: Co-treatment of RTKIs with indomethacin inhibited cell viability and AB1010-induced COX-2 expression resulting in decreased PGE2 production in tested TCC cells. Thus, COX inhibition may further potentiate RTKIs therapies in bladder cancer. Keywords: transitional cell carcinoma, axitinib, masitinib, cyclooxygenase-2, prostaglandin E2, indomethacin 

  1. Stem cell biology and cell transplantation therapy in the retina.

    Science.gov (United States)

    Osakada, Fumitaka; Hirami, Yasuhiko; Takahashi, Masayo

    2010-01-01

    Embryonic stem (ES) cells, which are derived from the inner cell mass of mammalian blastocyst stage embryos, have the ability to differentiate into any cell type in the body and to grow indefinitely while maintaining pluripotency. During development, cells undergo progressive and irreversible differentiation into specialized adult cell types. Remarkably, in spite of this restriction in potential, adult somatic cells can be reprogrammed and returned to the naive state of pluripotency found in the early embryo simply by forcing expression of a defined set of transcription factors. These induced pluripotent stem (iPS) cells are molecularly and functionally equivalent to ES cells and provide powerful in vitro models for development, disease, and drug screening, as well as material for cell replacement therapy. Since functional impairment results from cell loss in most central nervous system (CNS) diseases, recovery of lost cells is an important treatment strategy. Although adult neurogenesis occurs in restricted regions, the CNS has poor potential for regeneration to compensate for cell loss. Thus, cell transplantation into damaged or diseased CNS tissues is a promising approach to treating various neurodegenerative disorders. Transplantation of photoreceptors or retinal pigment epithelium cells derived from human ES cells can restore some visual function. Patient-specific iPS cells may lead to customized cell therapy. However, regeneration of retinal function will require a detailed understanding of eye development, visual system circuitry, and retinal degeneration pathology. Here, we review the current progress in retinal regeneration, focusing on the therapeutic potential of pluripotent stem cells.

  2. Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial.

    Science.gov (United States)

    Delgado, Elias; Perez-Basterrechea, Marcos; Suarez-Alvarez, Beatriz; Zhou, Huimin; Revuelta, Eva Martinez; Garcia-Gala, Jose Maria; Perez, Silvia; Alvarez-Viejo, Maria; Menendez, Edelmiro; Lopez-Larrea, Carlos; Tang, Ruifeng; Zhu, Zhenlong; Hu, Wei; Moss, Thomas; Guindi, Edward; Otero, Jesus; Zhao, Yong

    2015-12-01

    Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles. In this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the "educated" lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219. Clinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4(+) T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4(+) central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4(+) effector memory T cells (TEM) and CD8(+) TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C-C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function. Current clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects. Obra Social "La Caixa", Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de

  3. Application of Raman Spectroscopy and Univariate Modelling As a Process Analytical Technology for Cell Therapy Bioprocessing

    Science.gov (United States)

    Baradez, Marc-Olivier; Biziato, Daniela; Hassan, Enas; Marshall, Damian

    2018-01-01

    Cell therapies offer unquestionable promises for the treatment, and in some cases even the cure, of complex diseases. As we start to see more of these therapies gaining market authorization, attention is turning to the bioprocesses used for their manufacture, in particular the challenge of gaining higher levels of process control to help regulate cell behavior, manage process variability, and deliver product of a consistent quality. Many processes already incorporate the measurement of key markers such as nutrient consumption, metabolite production, and cell concentration, but these are often performed off-line and only at set time points in the process. Having the ability to monitor these markers in real-time using in-line sensors would offer significant advantages, allowing faster decision-making and a finer level of process control. In this study, we use Raman spectroscopy as an in-line optical sensor for bioprocess monitoring of an autologous T-cell immunotherapy model produced in a stirred tank bioreactor system. Using reference datasets generated on a standard bioanalyzer, we develop chemometric models from the Raman spectra for glucose, glutamine, lactate, and ammonia. These chemometric models can accurately monitor donor-specific increases in nutrient consumption and metabolite production as the primary T-cell transition from a recovery phase and begin proliferating. Using a univariate modeling approach, we then show how changes in peak intensity within the Raman spectra can be correlated with cell concentration and viability. These models, which act as surrogate markers, can be used to monitor cell behavior including cell proliferation rates, proliferative capacity, and transition of the cells to a quiescent phenotype. Finally, using the univariate models, we also demonstrate how Raman spectroscopy can be applied for real-time monitoring. The ability to measure these key parameters using an in-line Raman optical sensor makes it possible to have immediate

  4. Application of Raman Spectroscopy and Univariate Modelling As a Process Analytical Technology for Cell Therapy Bioprocessing.

    Science.gov (United States)

    Baradez, Marc-Olivier; Biziato, Daniela; Hassan, Enas; Marshall, Damian

    2018-01-01

    Cell therapies offer unquestionable promises for the treatment, and in some cases even the cure, of complex diseases. As we start to see more of these therapies gaining market authorization, attention is turning to the bioprocesses used for their manufacture, in particular the challenge of gaining higher levels of process control to help regulate cell behavior, manage process variability, and deliver product of a consistent quality. Many processes already incorporate the measurement of key markers such as nutrient consumption, metabolite production, and cell concentration, but these are often performed off-line and only at set time points in the process. Having the ability to monitor these markers in real-time using in-line sensors would offer significant advantages, allowing faster decision-making and a finer level of process control. In this study, we use Raman spectroscopy as an in-line optical sensor for bioprocess monitoring of an autologous T-cell immunotherapy model produced in a stirred tank bioreactor system. Using reference datasets generated on a standard bioanalyzer, we develop chemometric models from the Raman spectra for glucose, glutamine, lactate, and ammonia. These chemometric models can accurately monitor donor-specific increases in nutrient consumption and metabolite production as the primary T-cell transition from a recovery phase and begin proliferating. Using a univariate modeling approach, we then show how changes in peak intensity within the Raman spectra can be correlated with cell concentration and viability. These models, which act as surrogate markers, can be used to monitor cell behavior including cell proliferation rates, proliferative capacity, and transition of the cells to a quiescent phenotype. Finally, using the univariate models, we also demonstrate how Raman spectroscopy can be applied for real-time monitoring. The ability to measure these key parameters using an in-line Raman optical sensor makes it possible to have immediate

  5. Application of Raman Spectroscopy and Univariate Modelling As a Process Analytical Technology for Cell Therapy Bioprocessing

    Directory of Open Access Journals (Sweden)

    Marc-Olivier Baradez

    2018-03-01

    Full Text Available Cell therapies offer unquestionable promises for the treatment, and in some cases even the cure, of complex diseases. As we start to see more of these therapies gaining market authorization, attention is turning to the bioprocesses used for their manufacture, in particular the challenge of gaining higher levels of process control to help regulate cell behavior, manage process variability, and deliver product of a consistent quality. Many processes already incorporate the measurement of key markers such as nutrient consumption, metabolite production, and cell concentration, but these are often performed off-line and only at set time points in the process. Having the ability to monitor these markers in real-time using in-line sensors would offer significant advantages, allowing faster decision-making and a finer level of process control. In this study, we use Raman spectroscopy as an in-line optical sensor for bioprocess monitoring of an autologous T-cell immunotherapy model produced in a stirred tank bioreactor system. Using reference datasets generated on a standard bioanalyzer, we develop chemometric models from the Raman spectra for glucose, glutamine, lactate, and ammonia. These chemometric models can accurately monitor donor-specific increases in nutrient consumption and metabolite production as the primary T-cell transition from a recovery phase and begin proliferating. Using a univariate modeling approach, we then show how changes in peak intensity within the Raman spectra can be correlated with cell concentration and viability. These models, which act as surrogate markers, can be used to monitor cell behavior including cell proliferation rates, proliferative capacity, and transition of the cells to a quiescent phenotype. Finally, using the univariate models, we also demonstrate how Raman spectroscopy can be applied for real-time monitoring. The ability to measure these key parameters using an in-line Raman optical sensor makes it possible

  6. Potential feasibility of dental stem cells for regenerative therapies: stem cell transplantation and whole-tooth engineering.

    Science.gov (United States)

    Nakahara, Taka

    2011-07-01

    Multipotent mesenchymal stem cells from bone marrow are expected to be a somatic stem cell source for the development of new cell-based therapy in regenerative medicine. However, dental clinicians are unlikely to carry out autologous cell/tissue collection from patients (i.e., marrow aspiration) as a routine procedure in their clinics; hence, the utilization of bone marrow stem cells seems impractical in the dental field. Dental tissues harvested from extracted human teeth are well known to contain highly proliferative and multipotent stem cell compartments and are considered to be an alternative autologous cell source in cell-based medicine. This article provides a short overview of the ongoing studies for the potential application of dental stem cells and suggests the utilization of 2 concepts in future regenerative medicine: (1) dental stem cell-based therapy for hepatic and other systemic diseases and (2) tooth replacement therapy using the bioengineered human whole tooth, called the "test-tube dental implant." Regenerative therapies will bring new insights and benefits to the fields of clinical medicine and dentistry.

  7. Autologous Pluripotent Stem Cell-Derived β-Like Cells for Diabetes Cellular Therapy.

    Science.gov (United States)

    Millman, Jeffrey R; Pagliuca, Felicia W

    2017-05-01

    Development of stem cell technologies for cell replacement therapy has progressed rapidly in recent years. Diabetes has long been seen as one of the first applications for stem cell-derived cells because of the loss of only a single cell type-the insulin-producing β-cell. Recent reports have detailed strategies that overcome prior hurdles to generate functional β-like cells from human pluripotent stem cells in vitro, including from human induced pluripotent stem cells (hiPSCs). Even with this accomplishment, addressing immunological barriers to transplantation remains a major challenge for the field. The development of clinically relevant hiPSC derivation methods from patients and demonstration that these cells can be differentiated into β-like cells presents a new opportunity to treat diabetes without immunosuppression or immunoprotective encapsulation or with only targeted protection from autoimmunity. This review focuses on the current status in generating and transplanting autologous β-cells for diabetes cell therapy, highlighting the unique advantages and challenges of this approach. © 2017 by the American Diabetes Association.

  8. Adoptive T cell cancer therapy

    Science.gov (United States)

    Dzhandzhugazyan, Karine N.; Guldberg, Per; Kirkin, Alexei F.

    2018-06-01

    Tumour heterogeneity and off-target toxicity are current challenges of cancer immunotherapy. Karine Dzhandzhugazyan, Per Guldberg and Alexei Kirkin discuss how epigenetic induction of tumour antigens in antigen-presenting cells may form the basis for multi-target therapies.

  9. Stem cell therapy: From bench to bedside

    International Nuclear Information System (INIS)

    Tamarat, R.; Lataillade, J. J.; Bey, E.; Gourmelon, P.; Benderitter, M.

    2012-01-01

    Several countries have increased efforts to develop medical countermeasures to protect against radiation toxicity due to acts of bio-terrorism as well as cancer treatment. Both acute radiation injuries and delayed effects such as cutaneous effects and impaired wound repair depend, to some extent, on angiogenesis deficiency. Vascular damage influences levels of nutrients, oxygen available to skin tissue and epithelial cell viability. Consequently, the evolution of radiation lesions often becomes uncontrolled and surgery is the final option-amputation leading to a disability. Therefore, the development of strategies designed to promote healing of radiation injuries is a major therapeutic challenge. Adult mesenchymal stem cell therapy has been combined with surgery in some cases and not in others and successfully applied in patients with accidental radiation injuries. Although research in the field of radiation skin injury management has made substantial progress in the past 10 y, several strategies are still needed in order to enhance the beneficial effect of stem cell therapy and to counteract the deleterious effect of an irradiated tissue environment. This review summarises the current and evolving advances concerning basic and translational research based on stem cell therapy for the management of radiological burns. (authors)

  10. Cell-based therapies for chronic kidney disease

    NARCIS (Netherlands)

    van Koppen, A.N.

    2013-01-01

    Chronic kidney disease (CKD) may lead to end-stage renal failure, requiring renal replacement strategies. Development of new therapies to reduce progression of CKD is therefore a major global public health target. The aim of this thesis was to investigate whether cell-based therapies have the

  11. Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Mingchao Li

    Full Text Available Stem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED. Many relative animal studies have been done to evaluate the efficacy of this therapy in rats.This meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED.We searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP to mean arterial pressure (MAP and in the structure of the cavernous body were compared.10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001. In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS and neuronal nitric oxide synthase (nNOS, the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF. Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification.Our results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic

  12. Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

    Energy Technology Data Exchange (ETDEWEB)

    Tsuno, Hiroaki [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Yoshida, Toshiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nogami, Makiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Orthopedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Koike, Chika; Okabe, Motonori [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Noto, Zenko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Arai, Naoya; Noguchi, Makoto [Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nikaido, Toshio, E-mail: tnikaido@med.u-toyama.ac.jp [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan)

    2012-12-01

    Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAM{alpha} cells and induced to osteogenic status-their in vivo osteogenesis was subsequently investigated in rats. It was found that HAM{alpha} cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAM{alpha} cells. The expression of osteocalcin mRNA was increased in HAM{alpha} cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAM{alpha} cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: Black-Right-Pointing-Pointer Human amniotic mesenchymal cells include cells (HAM{alpha} cells) that have the properties of MSCs. Black-Right-Pointing-Pointer HAM{alpha} cells have excellent osteogenic differentiation potential. Black-Right-Pointing-Pointer Osteogenic differentiation ability of HAM{alpha} was amplified by calcium phosphate scaffolds. Black-Right-Pointing-Pointer HAM{alpha} cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

  13. Two different serum-free media and osmolality effect upon human 293 cell growth and adenovirus production.

    Science.gov (United States)

    Ferreira, Tiago B; Ferreira, Ana L; Carrondo, Manuel J T; Alves, Paula M

    2005-11-01

    Adenoviruses are promising vectors for gene therapy and vaccination protocols. Consequently, the market demands for adenovirus are increasing, driving the search for new methodologies for large-scale production of concentrated vectors with warranted purity and efficacy, in a cost-effective way. Nevertheless, the production of adenovirus is currently limited by the so-called 'cell density effect', i.e. a drop in cell specific productivity concomitant with increased cell concentration at infection. Of two different serum-free culture media (CD293 and EX-Cell), evaluated for their effect on human 293 cells growth and adenovirus production at cell densities higher than 1x10(6) cells/ml, EX-Cell proved the better medium for cell growth. Although adenovirus production was equivalent in both media when the infection was performed at 1x10(6) cells/ml, at 3x10(6) cells/ml CD293 was the better. This result related to the high ammonia content in EX-Cell medium at the highest cell concentration at infection. Besides this, the large-scale production of these vectors at high cell densities often requires re-feed strategies, which increase medium osmolality. While a negative effect on cell growth was observed with increasing osmolalities, adenovirus productivity was only affected for osmolalities higher than 430 mOsm.

  14. Proinflammatory interleukins' production by adipose tissue-derived mesenchymal stromal cells: the impact of cell culture conditions and cell-to-cell interaction.

    Science.gov (United States)

    Andreeva, Elena; Andrianova, Irina; Rylova, Julia; Gornostaeva, Aleksandra; Bobyleva, Polina; Buravkova, Ludmila

    2015-08-01

    The impact of culture conditions and interaction with activated peripheral blood mononuclear cells on the interleukin (IL) gene expression profile and proinflammatory IL-6 and IL-8 production by adipose-derived stromal cells (ASCs) was investigated. A microarray analysis revealed a wide range of IL genes either under standard (20%) or hypoxic (5%) O2 concentrations, some highly up-regulated at hypoxia. IL-6 and IL-8 production was inversely dependent on cell culture density. In early (first-third) passages, IL-6 and IL-8 concentration was higher at 20% O2 and in late (8th-12th) passages under 5% O2. Interaction between ASCs and mononuclear cells in indirect setting was accompanied with a significant decrease of IL-6 and did not result in the elevation of IL-8 concentration. Thereby, the production of proinflammatory interleukins (IL-6 and IL-8) may be affected by the ASC intrinsic features (density in culture, and duration of expansion), as well as by microenvironmental factors, such as hypoxia and the presence of blood-borne cells. These data are important for elucidating ASC paracrine activity regulation in vitro. They would also be on demand for optimisation of the cell therapy protocols, based on the application of ASC biologically active substances. SIGNIFICANCE PARAGRAPH: Ex vivo expansion is widely used for increasing the number of adipose-derived stromal cells (ASCs) and improving of their quality. The present study was designed to elucidate the particular factors influencing the interleukin production in ASCs. The presented data specified the parameters (i.e. cell density, duration of cultivation, hypoxia, etc.) that should be taken in mind when ASCs are intended to be used in protocols implying their paracrine activity. These data would be of considerable interest for researchers and clinicians working in the biomedical science. Copyright © 2015 John Wiley & Sons, Ltd.

  15. Introduction to solar cell production

    International Nuclear Information System (INIS)

    Kim, Gyeong Hae; Lee, Jun Sin

    2009-08-01

    This book introduces solar cell production. It is made up eight chapters, which are summary of solar cell with structure and prospect of the business, special variable of solar cell on light of the sun and factor causing variable of solar cell, production of solar cell with surface texturing, diffusion, metal printing dry and firing and edge isolation, process of solar cell on silicone wafer for solar cell, forming of electrodes, introduction of thin film solar cell on operating of solar cell, process of production and high efficiency of thin film solar cell, sorting of solar cell and production with background of silicone solar cell and thin film solar cell, structure and production of thin film solar cell and compound solar cell, introduction of solar cell module and the Industrial condition and prospect of solar cell.

  16. [Cell-based therapies - an innovative therapeutic option in ophthalmology: Treating corneal diseases with stem cells].

    Science.gov (United States)

    Bakker, Ann-Christin; Langer, Barbara

    2015-11-01

    Pathological changes and disorders of the cornea are a major cause of severe visual impairment and blindness. Replacement of a pathologically altered cornea with healthy corneal tissue from the eye of a suitable donor is among the most common and successful transplantation procedures in medicine. In Germany, approximately 5000-6000 corneal transplantations are performed each year, but the total demand per year is estimated to be twice as high. With a success rate of 90%, the outcome of cornea transplantation is very favourable. However, long-term maintenance and regeneration of a healthy new cornea requires tissue-specific corneal stem cells residing at the basal layer of the limbus, which is the annular transition zone between the cornea and sclera. When this important limbal stem cell population is destroyed or dysfunctional, a pathological condition known as limbal stem cell deficiency (LSCD) manifests. Limbal stem cell deficiency describes conditions associated with impaired corneal wound healing and regeneration. In this situation, transplantation of healthy limbal stem cells is the only curative treatment approach for restoration of an intact and functional ocular surface. To date, treatment of LSCD presents a great challenge for ophthalmologists. However, innovative, cell-therapeutic approaches may open new, promising treatment perspectives. In February 2015, the European Commission granted marketing authorization to the first stem cell-based treatment in the European Union. The product named Holoclar® is an advanced therapy medicinal product (ATMP) for the treatment of moderate to severe LSCD due to physical and chemical burns in adults. Further cell-based treatment approaches are in clinical development.

  17. Repair of Ischemic Injury by Pluripotent Stem Cell Based Cell Therapy without Teratoma through Selective Photosensitivity

    Directory of Open Access Journals (Sweden)

    Seung-Ju Cho

    2015-12-01

    Full Text Available Stem-toxic small molecules have been developed to induce selective cell death of pluripotent stem cells (PSCs to lower the risk of teratoma formation. However, despite their high efficacies, chemical-based approaches may carry unexpected toxicities on specific differentiated cell types. Herein, we took advantage of KillerRed (KR as a suicide gene, to selectively induce phototoxicity using visible light via the production of reactive oxygen species. PSCs in an undifferentiated state that exclusively expressed KR (KR-PSCs were eliminated by a single exposure to visible light. This highly selective cell death in KR-PSCs was exploited to successfully inhibit teratoma formation. In particular, endothelial cells from KR-mPSCs remained fully functional in vitro and sufficient to repair ischemic injury in vivo regardless of light exposure, suggesting that a genetic approach in which KR is expressed in a tightly controlled manner would be a viable strategy to inhibit teratoma formation for future safe PSC-based therapies.

  18. Suicidal gene therapy with rabbit cytochrome P450 4B1/4-ipomeanol, 2-aminoanthracene system in glioma cell

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Su Jin; Kang, Joo Hyun; Kim, Kwang Il; Lee, Tae Sup; Lee, Yong Jin; Woo, Kwang Sun; Chung, Wee Sup; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2010-10-15

    Suicidal gene therapy is based on the transduction of tumor cells with 'suicide' genes encoding for prodrugactivating enzymes that render target cells susceptible to prodrug treatment. Suicidal gene therapy results in the death of tumor with the expression of gene encoding enzyme that converts non-toxic prodrug into cytotoxic product. Cytochrome P450 4B1 (CYP4B1) activates 4- ipomeanol (4-ipo) and 2-aminoanthracene (2-AA) to cytotoxic furane epoxide and unsaturated dialdehyde intermediate. In this study, therapeutic effects of suicidal gene therapy with rabbit CYP4B1/4-ipo or CYP4B1/2-AA system

  19. Dental Stem Cell in Tooth Development and Advances of Adult Dental Stem Cell in Regenerative Therapies.

    Science.gov (United States)

    Tan, Jiali; Xu, Xin; Lin, Jiong; Fan, Li; Zheng, Yuting; Kuang, Wei

    2015-01-01

    Stem cell-based therapies are considered as a promising treatment for many clinical usage such as tooth regeneration, bone repairation, spinal cord injury, and so on. However, the ideal stem cell for stem cell-based therapy still remains to be elucidated. In the past decades, several types of stem cells have been isolated from teeth, including dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), dental follicle progenitor stem cells (DFPCs) and stem cells from apical papilla (SCAP), which may be a good source for stem cell-based therapy in certain disease, especially when they origin from neural crest is considered. In this review, the specific characteristics and advantages of the adult dental stem cell population will be summarized and the molecular mechanisms of the differentiation of dental stem cell during tooth development will be also discussed.

  20. Adoptive T cell therapy targeting CD1 and MR1

    Directory of Open Access Journals (Sweden)

    Tingxi eGuo

    2015-05-01

    Full Text Available Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential.

  1. Advances of reporter gene imaging monitoring stem cell therapy

    International Nuclear Information System (INIS)

    Pei Zhijun; Zhang Yongxue

    2010-01-01

    Stem cell transplantation in the treatment of various tissue damage or degenerative diseases are research hotspots both at home and abroad. However, ignorance of the homing, differentiation and functional expression of the stem cell in vivo influence the further development of stem cell therapy. As an important component of molecular imaging technology, reporter gene imaging dynamically monitors the change of stem cell in vivo via monitoring the expression of transfected reporter gene. This paper briefly describes the latest research progress and the future development trend of the monitoring of reporter gene imaging in stem cell therapy in vivo. (authors)

  2. Molecular Imaging in Stem Cell Therapy for Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Fahuan Song

    2014-01-01

    Full Text Available Spinal cord injury (SCI is a serious disease of the center nervous system (CNS. It is a devastating injury with sudden loss of motor, sensory, and autonomic function distal to the level of trauma and produces great personal and societal costs. Currently, there are no remarkable effective therapies for the treatment of SCI. Compared to traditional treatment methods, stem cell transplantation therapy holds potential for repair and functional plasticity after SCI. However, the mechanism of stem cell therapy for SCI remains largely unknown and obscure partly due to the lack of efficient stem cell trafficking methods. Molecular imaging technology including positron emission tomography (PET, magnetic resonance imaging (MRI, optical imaging (i.e., bioluminescence imaging (BLI gives the hope to complete the knowledge concerning basic stem cell biology survival, migration, differentiation, and integration in real time when transplanted into damaged spinal cord. In this paper, we mainly review the molecular imaging technology in stem cell therapy for SCI.

  3. ORAL-THERAPY FOR SMALL-CELL LUNG-CANCER

    NARCIS (Netherlands)

    POSTMUS, PE; SMIT, EF

    After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to

  4. Small cell carcinoma of the larynx: results of therapy

    International Nuclear Information System (INIS)

    Sole, J.; Juergens, A.; Musulen, E.; Lacasta, A.; Guedea, F.; Quer, M.; Leon, X.; Lopez Pousa, A.; Lerma, E.

    1994-01-01

    Small cell carcinoma is a rare malignant tumor of the larynx. Since this lesion was first described, only 58 cases have been reported in the literature. Between December 1985 and March 1992, five patients with small cell carcinoma of the larynx were treated at the Hospital de la Santa Creu i Sant Pau in Barcelona, Spain. One patient was treated with radiation therapy alone, three patients with chemotherapy and radiation therapy, and one patient with surgery, chemotherapy and radiation therapy. Local and distant control was achieved in only one patient who was observed for 12 months after radiation therapy. Four patients died, one of local disease without distant metastasis at 6 months following treatment, one of local and distant disease at 53 months after radiation therapy, and two of distant metastasis without local disease at 22 and 36 months following treatment. In spite of the fact that only one of the five patients presented in this series is alive and free of disease 12 months following treatment, recent published information suggests that chemotherapy and radiotherapy are currently the most effective form of therapy for small cell carcinoma of the larynx. 16 Refs

  5. T-Cell-Mediated Immune Responses in Patients with Cutaneous or Mucosal Leishmaniasis: Long-Term Evaluation after Therapy

    Science.gov (United States)

    Da-Cruz, Alda Maria; Bittar, Rita; Mattos, Marise; Oliveira-Neto, Manuel P.; Nogueira, Ricardo; Pinho-Ribeiro, Vanessa; Azeredo-Coutinho, Rilza Beatriz; Coutinho, Sergio G.

    2002-01-01

    T-cell immune responses in patients with cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) were studied during the active disease, at the end of therapy, and 1 to 17 years posttherapy (long-term follow-up). Lymphocyte proliferative responses, phenotypic characterization of CD4+ and CD8+ Leishmania-reactive T cells, and cytokine production were assayed. Patients with active ML and CL showed higher proportions of CD4+ than CD8+ T cells. In CL, the healing process was associated with a decrease of CD4+ and an increase of CD8+, leading to similar CD4+ and CD8+ proportions. This pattern was only seen in ML after long-term therapy. Long-term follow-up of patients with CL showed a positive CD4+/CD8+ ratio as observed during the active disease, although the percentages of these T cell subsets were significantly lower. Patients with CL did not show significant differences between gamma interferon (IFN-γ) and interleukin-5 (IL-5) production during the period of study. Patients with active ML presented higher IFN-γ and IL-5 levels compared to patients with active CL. IL-4 was only detected during active disease. Patients long term after cure from ML showed increasing production of IFN-γ, significant decrease of IL-5, and no IL-4 production. Two apparently beneficial immunological parameters were detected in tegumentary leishmaniasis: (i) decreasing proportions of CD4+ Leishmania-reactive T cells in the absence of IL-4 production associated with cure of CL and ML and (ii) decreasing levels of IL-5 long after cure, better detected in patients with ML. The observed T-cell responses maintained for a long period in healed patients could be relevant for immunoprotection against reinfection and used as a parameter for determining the prognosis of patients and selecting future vaccine preparations. PMID:11874860

  6. Human Embryonic Stem Cell Therapy in Crohn’s Disease: A Case Report

    Science.gov (United States)

    Shroff, Geeta

    2016-01-01

    Patient: Male, 21 Final Diagnosis: Crohn’s disease Symptoms: Intolerance to specific foods • abdominal pain and diarrhea Medication: Human embryonic stem cell therapy Clinical Procedure: Human embryonic stem cell transplantation Specialty: Gastroenterology Objective: Unusual or unexpected effect of treatment Background: Crohn’s disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565 000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn’s disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn’s disease. Case Report: A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Conclusions: Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn’s disease. PMID:26923312

  7. Cell-based therapies for cardiac repair : a meeting report on scientific observations and European regulatory viewpoints

    NARCIS (Netherlands)

    Schüssler-Lenz, Martina; Beuneu, Claire; Menezes-Ferreira, Margarida; Jekerle, Veronika; Bartunek, Jozef; Chamuleau, Steven; Celis, Patrick; Doevendans, Pieter; O'Donovan, Maura; Hill, Jonathan; Hystad, Marit; Jovinge, Stefan; Kyselovič, Ján; Lipnik-Stangelj, Metoda; Maciulaitis, Romaldas; Prasad, Krishna; Samuel, Anthony; Tenhunen, Olli; Tonn, Torsten; Rosano, Giuseppe; Zeiher, Andreas; Salmikangas, Paula

    In the past decade, novel cell-based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end-stage heart failure. Cardiac indications studied include acute

  8. Cell Death Pathways in Photodynamic Therapy of Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mroz, Pawel, E-mail: pmroz@partners.org [Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114 (United States); Department of Dermatology, Harvard Medical School, Boston, MA 02114 (United States); Yaroslavsky, Anastasia [Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114 (United States); Boston University College of Engineering, Boston, MA 02114 (United States); Kharkwal, Gitika B [Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114 (United States); Department of Dermatology, Harvard Medical School, Boston, MA 02114 (United States); Hamblin, Michael R. [Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114 (United States); Department of Dermatology, Harvard Medical School, Boston, MA 02114 (United States); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139 (United States)

    2011-06-03

    Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.

  9. Cell Death Pathways in Photodynamic Therapy of Cancer

    International Nuclear Information System (INIS)

    Mroz, Pawel; Yaroslavsky, Anastasia; Kharkwal, Gitika B; Hamblin, Michael R.

    2011-01-01

    Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT

  10. Mesenchymal Stromal Cell Therapy for Pancreatitis: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Sara M. Ahmed

    2018-01-01

    Full Text Available Background. Based on animal studies, adult mesenchymal stromal cells (MSCs are promising for the treatment of pancreatitis. However, the best type of this form of cell therapy and its mechanism of action remain unclear. Methods. We searched the PubMed, Web of Science, Scopus, Google Scholar, and Clinical Trials.gov websites for studies using MSCs as a therapy for both acute and chronic pancreatitis published until September 2017. Results. We identified 276 publications; of these publications, 18 met our inclusion criteria. In animal studies, stem cell therapy was applied more frequently for acute pancreatitis than for chronic pancreatitis. No clinical trials were identified. MSC therapy ameliorated pancreatic inflammation in acute pancreatitis and pancreatic fibrosis in chronic pancreatitis. Bone marrow and umbilical cord MSCs were the most frequently administered cell types. Due to the substantial heterogeneity among the studies regarding the type, source, and dose of MSCs used, conducting a meta-analysis was not feasible to determine the best type of MSCs. Conclusion. The available data were insufficient for determining the best type of MSCs for the treatment of acute or chronic pancreatitis; therefore, clinical trials investigating the use of MSCs as therapy for pancreatitis are not warranted.

  11. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke.

    Science.gov (United States)

    Wei, Ling; Wei, Zheng Z; Jiang, Michael Qize; Mohamad, Osama; Yu, Shan Ping

    2017-10-01

    One of the exciting advances in modern medicine and life science is cell-based neurovascular regeneration of damaged brain tissues and repair of neuronal structures. The progress in stem cell biology and creation of adult induced pluripotent stem (iPS) cells has significantly improved basic and pre-clinical research in disease mechanisms and generated enthusiasm for potential applications in the treatment of central nervous system (CNS) diseases including stroke. Endogenous neural stem cells and cultured stem cells are capable of self-renewal and give rise to virtually all types of cells essential for the makeup of neuronal structures. Meanwhile, stem cells and neural progenitor cells are well-known for their potential for trophic support after transplantation into the ischemic brain. Thus, stem cell-based therapies provide an attractive future for protecting and repairing damaged brain tissues after injury and in various disease states. Moreover, basic research on naïve and differentiated stem cells including iPS cells has markedly improved our understanding of cellular and molecular mechanisms of neurological disorders, and provides a platform for the discovery of novel drug targets. The latest advances indicate that combinatorial approaches using cell based therapy with additional treatments such as protective reagents, preconditioning strategies and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the characteristics of cell therapy in different ischemic models and the application of stem cells and progenitor cells as regenerative medicine for the treatment of stroke. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Stem cell therapies in preclinical models of stroke associated with aging

    Directory of Open Access Journals (Sweden)

    Aurel ePopa-Wagner

    2014-11-01

    Full Text Available Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.

  13. Stem cell therapy for cardiovascular disease : answering basic questions regarding cell behavior

    NARCIS (Netherlands)

    Bogt, Koen Elzert Adriaan van der

    2010-01-01

    Stem cell therapy has raised enthusiasm as a potential treatment for cardiovascular diseases. However, questions remain about the in vivo behavior of the cells after transplantation and the mechanism of action with which the cells could potentially alleviate disease symptoms. The objective of the

  14. Stem cell therapy for retinal diseases

    Science.gov (United States)

    Garcia, José Mauricio; Mendonça, Luisa; Brant, Rodrigo; Abud, Murilo; Regatieri, Caio; Diniz, Bruno

    2015-01-01

    In this review, we discuss about current knowledge about stem cell (SC) therapy in the treatment of retinal degeneration. Both human embryonic stem cell and induced pluripotent stem cell has been growth in culture for a long time, and started to be explored in the treatment of blinding conditions. The Food and Drug Administration, recently, has granted clinical trials using SC retinal therapy to treat complex disorders, as Stargardt’s dystrophy, and patients with geographic atrophy, providing good outcomes. This study’s intent is to overview the critical regeneration of the subretinal anatomy through retinal pigment epithelium transplantation, with the goal of reestablish important pathways from the retina to the occipital cortex of the brain, as well as the differentiation from pluripotent quiescent SC to adult retina, and its relationship with a primary retinal injury, different techniques of transplantation, management of immune rejection and tumorigenicity, its potential application in improving patients’ vision, and, finally, approaching future directions and challenges for the treatment of several conditions. PMID:25621115

  15. Embryonic stem cell therapy of heart failure in genetic cardiomyopathy.

    Science.gov (United States)

    Yamada, Satsuki; Nelson, Timothy J; Crespo-Diaz, Ruben J; Perez-Terzic, Carmen; Liu, Xiao-Ke; Miki, Takashi; Seino, Susumu; Behfar, Atta; Terzic, Andre

    2008-10-01

    Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K(+) (K(ATP)) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K(ATP) channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. Disclosure of potential conflicts of interest is

  16. Osteosarcoma: Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies

    Directory of Open Access Journals (Sweden)

    Ander Abarrategi

    2016-01-01

    Full Text Available Osteosarcoma (OS is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs.

  17. Ethical and Safety Issues of Stem Cell-Based Therapy.

    Science.gov (United States)

    Volarevic, Vladislav; Markovic, Bojana Simovic; Gazdic, Marina; Volarevic, Ana; Jovicic, Nemanja; Arsenijevic, Nebojsa; Armstrong, Lyle; Djonov, Valentin; Lako, Majlinda; Stojkovic, Miodrag

    2018-01-01

    Results obtained from completed and on-going clinical studies indicate huge therapeutic potential of stem cell-based therapy in the treatment of degenerative, autoimmune and genetic disorders. However, clinical application of stem cells raises numerous ethical and safety concerns. In this review, we provide an overview of the most important ethical issues in stem cell therapy, as a contribution to the controversial debate about their clinical usage in regenerative and transplantation medicine. We describe ethical challenges regarding human embryonic stem cell (hESC) research, emphasizing that ethical dilemma involving the destruction of a human embryo is a major factor that may have limited the development of hESC-based clinical therapies. With previous derivation of induced pluripotent stem cells (iPSCs) this problem has been overcome, however current perspectives regarding clinical translation of iPSCs still remain. Unlimited differentiation potential of iPSCs which can be used in human reproductive cloning, as a risk for generation of genetically engineered human embryos and human-animal chimeras, is major ethical issue, while undesired differentiation and malignant transformation are major safety issues. Although clinical application of mesenchymal stem cells (MSCs) has shown beneficial effects in the therapy of autoimmune and chronic inflammatory diseases, the ability to promote tumor growth and metastasis and overestimated therapeutic potential of MSCs still provide concerns for the field of regenerative medicine. This review offers stem cell scientists, clinicians and patient's useful information and could be used as a starting point for more in-depth analysis of ethical and safety issues related to clinical application of stem cells.

  18. Autologous blood cell therapies from pluripotent stem cells

    Science.gov (United States)

    Lengerke, Claudia; Daley, George Q.

    2010-01-01

    Summary The discovery of human embryonic stem cells (hESCs) raised promises for a universal resource for cell based therapies in regenerative medicine. Recently, fast-paced progress has been made towards the generation of pluripotent stem cells (PSCs) amenable for clinical applications, culminating in reprogramming of adult somatic cells to autologous PSCs that can be indefinitely expanded in vitro. However, besides the efficient generation of bona fide, clinically safe PSCs (e.g. without the use of oncoproteins and gene transfer based on viruses inserting randomly into the genome), a major challenge in the field remains how to efficiently differentiate PSCs to specific lineages and how to select for cells that will function normally upon transplantation in adults. In this review, we analyse the in vitro differentiation potential of PSCs to the hematopoietic lineage discussing blood cell types that can be currently obtained, limitations in derivation of adult-type HSCs and prospects for clinical application of PSCs-derived blood cells. PMID:19910091

  19. Clinical cell therapy guidelines for neurorestoration (China version 2016

    Directory of Open Access Journals (Sweden)

    Huang H

    2017-02-01

    Full Text Available Hongyun Huang,1 Lin Chen,2 Qingyan Zou,3 Fabin Han,4 Tiansheng Sun,5 Gengsheng Mao,1 Xijing He6 1Institute of Neurorestoratology, General Hospital of Armed Police Forces, 2Department of Neurosurgery, Yuquan Hospital, Tsinghua University, Beijing, 3Guangdong 999 Brain Hospital, Guangzhou, 4Centre for Stem Cells and Regenerative Medicine, Affiliated Hospital of Taishan Medical University, Liaocheng, Shandong, 5Department of Orthopedics, Beijing Army General Hospital, Beijing, 6Second Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China On behalf of the Chinese Association of Neurorestoratology and Chinese Branch of the International Association of Neurorestoratology Abstract: Cell therapy has been shown to be a key clinical therapeutic option for central ­nervous system disease or damage, and >30 types of cells have been identified through preclinical studies as having the capacity for neurorestoration. To standardize the clinical procedures of cell therapy as one of the strategies for treating neurological disorders, the first set of guidelines governing the clinical application of neurorestoration was completed in 2011 by the Chinese Branch of the International Association of Neurorestoratology. Given the rapidly advancing state of the field, the Neurorestoratology Professional Committee of Chinese Medical Doctor Association (Chinese Association of Neurorestoratology and the Chinese Branch of the International Association of Neurorestoratology have approved the current version known as the “Clinical Cell Therapy Guidelines for Neurorestoration (China Version 2016”. We hope this guideline will reflect the most recent results demonstrated in preclinical research, transnational studies, and evidence-based clinical studies, as well as guide clinical practice in applying cell therapy for neurorestoration. Keywords: cell therapy, neurorestoration, China, clinical

  20. Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

    Science.gov (United States)

    Yoshida, Toshiyuki; Washio, Kaoru; Iwata, Takanori; Okano, Teruo; Ishikawa, Isao

    2012-01-01

    It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy. PMID:22315604

  1. Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

    Directory of Open Access Journals (Sweden)

    Toshiyuki Yoshida

    2012-01-01

    Full Text Available It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy.

  2. Rationale and Design of the First Double-Blind, Placebo-Controlled Trial with Allogeneic Adipose Tissue-Derived Stromal Cell Therapy in Patients with Ischemic Heart Failure

    DEFF Research Database (Denmark)

    Kastrup, Jens; Schou, Morten; Gustafsson, Ida

    2017-01-01

    BACKGROUND: Ischemic heart failure (IHF) has a poor prognosis in spite of optimal therapy. We have established a new allogeneic Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors. It is produced without animal products, in closed bioreactor systems...

  3. Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement.

    Science.gov (United States)

    Di Foggia, Valentina; Makwana, Priyanka; Ali, Robin R; Sowden, Jane C

    2016-06-01

    Stem cell therapies are being explored as potential treatments for retinal disease. How to replace neurons in a degenerated retina presents a continued challenge for the regenerative medicine field that, if achieved, could restore sight. The major issues are: (i) the source and availability of donor cells for transplantation; (ii) the differentiation of stem cells into the required retinal cells; and (iii) the delivery, integration, functionality, and survival of new cells in the host neural network. This review considers the use of induced pluripotent stem cells (iPSC), currently under intense investigation, as a platform for cell transplantation therapy. Moreover, patient-specific iPSC are being developed for autologous cell transplantation and as a tool for modeling specific retinal diseases, testing gene therapies, and drug screening.

  4. Magnetic resonance imaging and cell-based neurorestorative therapy after brain injury

    Directory of Open Access Journals (Sweden)

    Quan Jiang

    2016-01-01

    Full Text Available Restorative cell-based therapies for experimental brain injury, such as stroke and traumatic brain injury, substantially improve functional outcome. We discuss and review state of the art magnetic resonance imaging methodologies and their applications related to cell-based treatment after brain injury. We focus on the potential of magnetic resonance imaging technique and its associated challenges to obtain useful new information related to cell migration, distribution, and quantitation, as well as vascular and neuronal remodeling in response to cell-based therapy after brain injury. The noninvasive nature of imaging might more readily help with translation of cell-based therapy from the laboratory to the clinic.

  5. Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring

    DEFF Research Database (Denmark)

    Wingstrand, Vibe Lindeblad; Larsen, Christian Grønhøj; Jensen, David H

    2016-01-01

    OBJECTIVES: Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance...... the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. DATA SOURCES: PubMed, Embase, the Cochrane Library and Google Scholar were searched. METHODS: Controlled studies that assessed...... the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. RESULTS: Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic...

  6. Application of stem cell/growth factor system, as a multimodal therapy approach in regenerative medicine to improve cell therapy yields.

    Science.gov (United States)

    Pourrajab, Fatemeh; Babaei Zarch, Mojtaba; Baghi Yazdi, Mohammad; Rahimi Zarchi, Abolfazl; Vakili Zarch, Abbas

    2014-04-15

    Stem cells hold a great promise for regenerative medicine, especially for replacing cells in infarcted organ that hardly have any intrinsic renewal capacity, including heart and brain. Signaling pathways that regulate pluripotency or lineage-specific gene and protein expression have been the major focus of stem cell research. Between them, there are some well known signaling pathways such as GF/GFR systems, SDF-1α/CXC4 ligand receptor interaction and PI3K/Akt signaling, and cytokines may regulate cell fate decisions, and can be utilized to positively influence cell therapy outcomes or accentuate synergistic compliance. For example, contributing factors in the progression of heart failure are both the loss of cardiomyocytes after myocardial infarction, and the absence of an adequate endogenous repair signaling. Combining cell engraftment with therapeutic signaling factor delivery is more exciting in terms of host progenitor/donor stem cell survival and proliferation. Thus stem cell-based therapy, besides triggering signaling pathways through GF/GFR systems can become a realistic option in regenerative processes for replacing lost cells and reconstituting the damaged organ, as before. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Therapy strategy for intracranial germ-cell tumours and initial results of the GPO therapy study MAKEI 86

    International Nuclear Information System (INIS)

    Goebel, U.; Calaminus, G.; Haasenritter, N.

    1988-01-01

    Pineal tumours are increasingly identified histologically since the introduction of the surgical microscope and microsurgical techniques. A major biological characteristic of germ-cell tumours is the fact that they produce tumour markers. Meaningful therapy planning is determined by the biological behaviour of the individual tumour entity which is strongly influenced by its intracranial localization. Important risk factors need to be identified and weighted according to previous treatment in order to arrive at an adequate therapy with improved curative prospects. Three risk areas can be defined for tumour extension. Therapy planning is also determined by the metastatic spread behaviour of germ-cell tumours. Within the two therapy studies for nontesticular germ-cell tumours MAKEI 83 and 86, a total of 180 germ-cell tumours, 24 of which were localized intercranially, were reported from 46 different clinics. All patients have a survival probability according to Kaplan and Meier of 67 ± 10% at an observation duration of 48 months. (orig./MG) [de

  8. Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion.

    Science.gov (United States)

    Park, Susanna S

    2016-04-01

    Retinal vascular conditions, such as diabetic retinopathy and retinal vein occlusion, remain leading causes of vision loss. No therapy exists to restore vision loss resulting from retinal ischemia and associated retinal degeneration. Tissue regeneration is possible with cell therapy. The goal would be to restore or replace the damaged retinal vasculature and the retinal neurons that are damaged and/or degenerating from the hypoxic insult. Currently, various adult cell therapies have been explored as potential treatment. They include mesenchymal stem cells, vascular precursor cells (i.e., CD34+ cells, hematopoietic cells or endothelial progenitor cells), and adipose stromal cells. Preclinical studies show that all these cells have a paracrine trophic effect on damaged ischemic tissue, leading to tissue preservation. Endothelial progenitor cells and adipose stromal cells integrate into the damaged retinal vascular wall in preclinical models of diabetic retinopathy and ischemia-reperfusion injury. Mesenchymal stem cells do not integrate as readily but appear to have a primary paracrine trophic effect. Early phase clinical trials have been initiated and ongoing using mesenchymal stem cells or autologous bone marrow CD34+ cells injected intravitreally as potential therapy for diabetic retinopathy or retinal vein occlusion. Adipose stromal cells or pluripotent stem cells differentiated into endothelial colony-forming cells have been explored in preclinical studies and show promise as possible therapies for retinal vascular disorders. The relative safety or efficacy of these various cell therapies for treating retinal vascular disorders have yet to be determined.

  9. Clinical Development and Commercialization of Advanced Therapy Medicinal Products in the European Union: How Are the Product Pipeline and Regulatory Framework Evolving?

    Science.gov (United States)

    Boráň, Tomáš; Menezes-Ferreira, Margarida; Reischl, Ilona; Celis, Patrick; Ferry, Nicolas; Gänsbacher, Bernd; Krafft, Hartmut; Lipucci di Paola, Michele; Sladowski, Dariusz; Salmikangas, Paula

    2017-09-01

    The research and development of advanced therapy medicinal products (ATMPs) has been active in Europe and worldwide during recent years. Yet, the number of licensed products remains low. The main expected legal change in the near future in the European Union (EU) concerns the regulation on clinical trials (536/2014), which will come into force in 2018. With this new framework, a more harmonized and swift process for approval of clinical trials is anticipated, which is expected to support the entry of new innovations into the EU market. A survey on ATMPs in clinical trials during 2010-2015 in the EU was conducted in order to study the trends of ATMP development since the earlier survey published in 2012. According to the results, the number of clinical trials using ATMPs is slowly increasing in the EU. Yet, the focus is still in early development, and the projects are mainly carried out by small and medium-sized enterprises, academia, and hospitals. Oncology is the main area of clinical development. Yet, the balance between cell-based products and gene therapy medicinal products in this area may be changing in the future due to the new T-cell technologies. Many limitations and challenges are identified for ATMP development, requiring proportionate regulatory requirements. On the other hand, for such a novel field, the developers should be active in considering possible constraints and actively engage with authorities to look for solutions. This article provides up to-date information on forthcoming regulatory improvements and discusses the main challenges hampering the commercialization of ATMPs in the EU.

  10. Chimeric antigen receptors for adoptive T cell therapy in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Mingxue Fan

    2017-08-01

    Full Text Available Abstract Currently, conventional therapies for acute myeloid leukemia (AML have high failure and relapse rates. Thus, developing new strategies is crucial for improving the treatment of AML. With the clinical success of anti-CD19 chimeric antigen receptor (CAR T cell therapies against B-lineage malignancies, many studies have attempted to translate the success of CAR T cell therapy to other malignancies, including AML. This review summarizes the current advances in CAR T cell therapy against AML, including preclinical studies and clinical trials, and discusses the potential AML-associated surface markers that could be used for further CAR technology. Finally, we describe strategies that might address the current issues of employing CAR T cell therapy in AML.

  11. Stem cell therapy and its potential role in pituitary disorders.

    Science.gov (United States)

    Lara-Velazquez, Montserrat; Akinduro, Oluwaseun O; Reimer, Ronald; Woodmansee, Whitney W; Quinones-Hinojosa, Alfredo

    2017-08-01

    The pituitary gland is one of the key components of the endocrine system. Congenital or acquired alterations can mediate destruction of cells in the gland leading to hormonal dysfunction. Even though pharmacological treatment for pituitary disorders is available, exogenous hormone replacement is neither curative nor sustainable. Thus, alternative therapies to optimize management and improve quality of life are desired. An alternative modality to re-establish pituitary function is to promote endocrine cell regeneration through stem cells that can be obtained from the pituitary parenchyma or pluripotent cells. Stem cell therapy has been successfully applied to a plethora of other disorders, and is a promising alternative to hormonal supplementation for resumption of normal hormone homeostasis. In this review, we describe the common causes for pituitary deficiencies and the advances in cellular therapy to restore the physiological pituitary function.

  12. Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany.

    Science.gov (United States)

    Renner, Matthias; Anliker, Brigitte; Sanzenbacher, Ralf; Schuele, Silke

    2015-01-01

    In the European Union, clinical trials for Advanced Therapy Medicinal Products are regulated at the national level, in contrast to the situation for a Marketing Authorisation Application, in which a centralised procedure is foreseen for these medicinal products. Although based on a common understanding regarding the regulatory requirement to be fulfilled before conduct of a clinical trial with an Advanced Therapy Investigational Medicinal Product, the procedures and partly the scientific requirements for approval of a clinical trial application differ between the European Union Member States. This chapter will thus give an overview about the path to be followed for a clinical trial application and the subsequent approval process for an Advanced Therapy Investigational Medicinal Product in Germany and will describe the role of the stakeholders that are involved. In addition, important aspects of manufacturing, quality control and non-clinical testing of Advanced Therapy Medicinal Products in the clinical development phase are discussed. Finally, current and future approaches for harmonisation of clinical trial authorisation between European Union Member States are summarised.

  13. Engineered T Cells for the Adoptive Therapy of B-Cell Chronic Lymphocytic Leukaemia

    Directory of Open Access Journals (Sweden)

    Philipp Koehler

    2012-01-01

    Full Text Available B-cell chronic lymphocytic leukaemia (B-CLL remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19+ leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19+ B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

  14. Stem Cell Therapy for Myocardial Infarction: Are We Missing Time?

    NARCIS (Netherlands)

    ter Horst, Kasper W.

    2010-01-01

    The success of stem cell therapy in myocardial infarction (MI) is modest, and for stem cell therapy to be clinically effective fine-tuning in regard to timing, dosing, and the route of administration is required. Experimental studies suggest the existence of a temporal window of opportunity bound by

  15. Stem Cells and Herbal Acupuncture Therapy

    Directory of Open Access Journals (Sweden)

    Ki Rok Kwon

    2005-12-01

    Full Text Available Stem cell therapy implies the birth of regenerative medicine. Regenerative medicine signify treatment through regeneration of cells which was impossible by existing medicine. Stem cell is classified into embryonic stem cell and adult stem cell and they have distinctive benefits and limitations. Researches on stem cell are already under active progression and is expected to be commercially available in the near future. One may not relate the stem cell treatment with Oriental medicine, but can be interpreted as the fundamental treatment action of Oriental medicine is being investigated in more concrete manner. When it comes to difficult to cure diseases, there is no boundary between eastern and western medicine, and one must be ready to face and overcome changes lying ahead.

  16. Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells.

    Science.gov (United States)

    Li, Yao; Chan, Lawrence; Nguyen, Huy V; Tsang, Stephen H

    2016-01-01

    Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.

  17. Radiation Therapy of Suprasellar Germ Cell Tumors

    International Nuclear Information System (INIS)

    Park, Woo Yoon; Choi, Doo Ho; Choi, Eun Kyung; Kim, Il Han; Ha, Sung Whan; Park, Charn Il

    1988-01-01

    A retrospective study was performed on 15 patients with suprasellar germ cell tumors treated by megavoltage external beam irradiation between Feb. 1979 and Dec. 1985. Follow-up period of survivors was 30 to 91 months. Histologic diagnosis was obtained before radiation therapy in 10 patients (9 germinomas and 1 mixed). Five patients were treated without histologic verification. In 9 patients with biopsy-proven germinomas radiation therapy was delivered to the craniospinal axis in 6, to the whole brain in 3. In 5 patients with mixed germ cell tumor or elevated tumor marker, irradiation was delivered to the craniospinal axis in 2, to the whole brain in 2, and to the primary site only in 1. Total doses ranged from 5,000 to 5,500 cGy to the primary site, 3,000 to 4,400 cGy to the whole brain, and 1,300 to 3,000 cGy to the spine. In these 14, local tumor was controlled and primary or spinal failure was not observed. One patient without elevated tumor marker was treated to the whole brain, The tumor was not controlled and he had spinal recurrence. It is proven that radiation therapy is an effective treatment for suprasellar germ cell tumors. The neuroendocrinologic presentation, tumor marker status, early response to radiation measured on CT seem to be useful means for selecting patients for radiation therapy when tissue diagnosis is not available

  18. Cell therapy for spinal cord injury informed by electromagnetic waves.

    Science.gov (United States)

    Finnegan, Jack; Ye, Hui

    2016-10-01

    Spinal cord injury devastates the CNS, besetting patients with symptoms including but not limited to: paralysis, autonomic nervous dysfunction, pain disorders and depression. Despite the identification of several molecular and genetic factors, a reliable regenerative therapy has yet to be produced for this terminal disease. Perhaps the missing piece of this puzzle will be discovered within endogenous electrotactic cellular behaviors. Neurons and stem cells both show mediated responses (growth rate, migration, differentiation) to electromagnetic waves, including direct current electric fields. This review analyzes the pathophysiology of spinal cord injury, the rationale for regenerative cell therapy and the evidence for directing cell therapy via electromagnetic waves shown by in vitro experiments.

  19. Steady advance of stem cell therapies: report from the 2011 World Stem Cell Summit, Pasadena, California, October 3-5.

    Science.gov (United States)

    Swan, Melanie

    2011-12-01

    Stem cell research and related therapies (including regenerative medicine and cellular therapies) could have a significant near-term impact on worldwide public health and aging. One reason is the industry's strong linkage between policy, science, industry, and patient advocacy, as was clear in the attendance and programming at the 7(th) annual World Stem Cell Summit held in Pasadena, California, October 3-5, 2011. A special conference session sponsored by the SENS Foundation discussed how stem cell therapies are being used to extend healthy life span. Stem cells are useful not only in cell-replacement therapies, but also in disease modeling, drug discovery, and drug toxicity screening. Stem cell therapies are currently being applied to over 50 diseases, including heart, lung, neurodegenerative, and eye disease, cancer, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Dozens of companies are developing therapeutic solutions that are in different stages of clinical use and clinical trials. Some high-profile therapies include Dendreon's Provenge for prostate cancer, Geron's first-ever embryonic stem cell trials for spinal cord injury, Fibrocell's laViv cellular therapy for wrinkles, and well-established commercial skin substitutes (Organogenesis' Apligraf and Advanced BioHealing's Dermagraft). Stem cell policy issues under consideration include medical tourism, standards for large-scale stem cell manufacturing, and lingering ethical debates over the use of embryonic stem cells. Contemporary stem cell science advances include a focus on techniques for the direct reprogramming of cells from one lineage to another without returning to pluripotency as an intermediary step, improved means of generating and characterizing induced pluripotent cells, and progress in approaches to neurodegenerative disease.

  20. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

    Directory of Open Access Journals (Sweden)

    Ellebaek Eva

    2012-08-01

    Full Text Available Abstract Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL, in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625 including patients with metastatic melanoma, PS ≤1, age Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months, 2 patients had stable disease (4 and 5 months and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

  1. Mesenchymal stem cells: cell biology and potential use in therapy

    DEFF Research Database (Denmark)

    Kassem, Moustapha; Kristiansen, Malthe; Abdallah, Basem M

    2004-01-01

    Mesenchymal stem cells are clonogenic, non-haematopoietic stem cells present in the bone marrow and are able to differentiate into multiple mesoderm-type cell lineages e.g. osteoblasts, chondrocytes, endothelial-cells and also non-mesoderm-type lineages e.g. neuronal-like cells. Several methods...... are currently available for isolation of the mesenchymal stem cells based on their physical and immunological characteristics. Because of the ease of their isolation and their extensive differentiation potential, mesenchymal stem cells are among the first stem cell types to be introduced in the clinic. Recent...... studies have demonstrated that the life span of mesenchymal stem cells in vitro can be extended by increasing the levels of telomerase expression in the cells and thus allowing culture of large number of cells needed for therapy. In addition, it has been shown that it is possible to culture the cells...

  2. Strategies for fuel cell product development. Developing fuel cell products in the technology supply chain

    International Nuclear Information System (INIS)

    Hellman, H.L.

    2004-01-01

    Due to the high cost of research and development and the broad spectrum of knowledge and competences required to develop fuel cell products, many product-developing firms outsource fuel cell technology, either partly or completely. This article addresses the inter-firm process of fuel cell product development from an Industrial Design Engineering perspective. The fuel cell product development can currently be characterised by a high degree of economic and technical uncertainty. Regarding the technology uncertainty: product-developing firms are more often then not unfamiliar with fuel cell technology technology. Yet there is a high interface complexity between the technology supplied and the product in which it is to be incorporated. In this paper the information exchange in three current fuel cell product development projects is analysed to determine the information required by a product designer to develop a fuel cell product. Technology transfer literature suggests that transfer effectiveness is greatest when the type of technology (technology uncertainty) and the type of relationship between the technology supplier and the recipient are carefully matched. In this line of thinking this paper proposes that the information required by a designer, determined by the design strategy and product/system volume, should be met by an appropriate level of communication interactivity with a technology specialist. (author)

  3. T-cell Responses in the Microenvironment of Primary Renal Cell Carcinoma-Implications for Adoptive Cell Therapy

    DEFF Research Database (Denmark)

    Andersen, Rikke; Westergaard, Marie Christine Wulff; Kjeldsen, Julie Westerlin

    2018-01-01

    In vitro expansion of large numbers of highly potent tumor-reactive T cells appears a prerequisite for effective adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TIL) as shown in metastatic melanoma (MM). We therefore sought to determine whether renal cell carcinomas (RCC...

  4. NanOx, a new model to predict cell survival in the context of particle therapy

    Science.gov (United States)

    Cunha, M.; Monini, C.; Testa, E.; Beuve, M.

    2017-02-01

    Particle therapy is increasingly attractive for the treatment of tumors and the number of facilities offering it is rising worldwide. Due to the well-known enhanced effectiveness of ions, it is of utmost importance to plan treatments with great care to ensure tumor killing and healthy tissues sparing. Hence, the accurate quantification of the relative biological effectiveness (RBE) of ions, used in the calculation of the biological dose, is critical. Nevertheless, the RBE is a complex function of many parameters and its determination requires modeling. The approaches currently used have allowed particle therapy to thrive, but still show some shortcomings. We present herein a short description of a new theoretical framework, NanOx, to calculate cell survival in the context of particle therapy. It gathers principles from existing approaches, while addressing some of their weaknesses. NanOx is a multiscale model that takes the stochastic nature of radiation at nanometric and micrometric scales fully into account, integrating also the chemical aspects of radiation-matter interaction. The latter are included in the model by means of a chemical specific energy, determined from the production of reactive chemical species induced by irradiation. Such a production represents the accumulation of oxidative stress and sublethal damage in the cell, potentially generating non-local lethal events in NanOx. The complementary local lethal events occur in a very localized region and can, alone, lead to cell death. Both these classes of events contribute to cell death. The comparison between experimental data and model predictions for the V79 cell line show a good agreement. In particular, the dependence of the typical shoulders of cell survival curves on linear energy transfer are well described, but also the effectiveness of different ions, including the overkill effect. These results required the adjustment of a number of parameters compatible with the application of the model in

  5. Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells

    OpenAIRE

    Yang, Ke; Wang, Xiao Qun; He, Yu Song; Lu, Lin; Chen, Qiu Jing; Liu, Jing; Shen, Wei Feng

    2010-01-01

    Abstract Background Advanced glycation products (AGEs), as endogenous inflammatory mediator, compromise the physiological function of mesenchymal stem cells (MSCs). MSCs have a potential role in cell replacement therapy in acute myocardial infarction and ischemic cardiomyopathy. However, mechanisms of AGEs on MSCs are still not unveiled. Methods Reactive oxygen species (ROS), genes regulation, cell proliferation and migration have been detected by AGE-BSA stimulated MSCs. Results We found tha...

  6. Chimeric antigen receptor T cells: a novel therapy for solid tumors

    Directory of Open Access Journals (Sweden)

    Shengnan Yu

    2017-03-01

    Full Text Available Abstract The chimeric antigen receptor T (CAR-T cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2, and mesothelin (MSLN, as well as the challenges for CAR-T cell therapy.

  7. Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy

    Science.gov (United States)

    2013-10-01

    SUBTITLE Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy 5a. CONTRACT NUMBER Subproject 1: Muscle Stem Cell Therapy...various muscle diseases, including Duchenne muscular dystrophy (DMD), develop progressive cardiomyopathy. Cellular cardiomyoplasty, which involves the

  8. Metabolic flux profiling of MDCK cells during growth and canine adenovirus vector production

    OpenAIRE

    Nuno Carinhas; Daniel A. M. Pais; Alexey Koshkin; Paulo Fernandes; Ana S. Coroadinha; Manuel J. T. Carrondo; Paula M. Alves; Ana P. Teixeira

    2016-01-01

    Canine adenovirus vector type 2 (CAV2) represents an alternative to human adenovirus vectors for certain gene therapy applications, particularly neurodegenerative diseases. However, more efficient production processes, assisted by a greater understanding of the effect of infection on producer cells, are required. Combining [1,2-13C]glucose and [U-13C]glutamine, we apply for the first time 13C-Metabolic flux analysis (13C-MFA) to study E1-transformed Madin-Darby Canine Kidney (MDCK) cells meta...

  9. Critical elements in the development of cell therapy potency assays for ischemic conditions.

    Science.gov (United States)

    Porat, Yael; Abraham, Eytan; Karnieli, Ohad; Nahum, Sagi; Woda, Juliana; Zylberberg, Claudia

    2015-07-01

    A successful potency assay for a cell therapy product (CTP) used in the treatment of ischemic conditions should quantitatively measure relevant biological properties that predict therapeutic activity. This is especially challenging because of numerous degrees of complexity stemming from factors that include a multifactorial complex mechanism of action, cell source, inherent cell characteristics, culture method, administration mode and the in vivo conditions to which the cells are exposed. The expected biological function of a CTP encompasses complex interactions that range from a biochemical, metabolic or immunological activity to structural replacement of damaged tissue or organ. Therefore, the requirements for full characterization of the active substance with respect to biological function could be taxing. Moreover, the specific mechanism of action is often difficult to pinpoint to a specific molecular entity; rather, it is more dependent on the functionality of the cellular components acting in a in a multifactorial fashion. In the case of ischemic conditions, the cell therapy mechanism of action can vary from angiogenesis, vasculogenesis and arteriogenesis that may activate different pathways and clinical outcomes. The CTP cellular attributes with relation to the suggested mechanism of action can be used for the development of quantitative and reproducible analytical potency assays. CTPs selected and released on the basis of such potency assays should have the highest probability of providing meaningful clinical benefit for patients. This White Paper will discuss and give examples for key elements in the development of a potency assay for treatment of ischemic disorders treated by the use of CTPs. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  10. Clinical Grade Regulatory CD4+ T Cells (Tregs: Moving Toward Cellular-Based Immunomodulatory Therapies

    Directory of Open Access Journals (Sweden)

    Richard Duggleby

    2018-02-01

    Full Text Available Regulatory T cells (Tregs are CD4+ T cells that are key players of immune tolerance. They are powerful suppressor cells, able to impact the function of numerous immune cells, including key effectors of inflammation such as effector T cells. For this reason, Tregs are an ideal candidate for the development of cell therapy approaches to modulate immune responses. Treg therapy has shown promising results so far, providing key knowledge on the conditions in which these cells can provide protection and demonstrating that they could be an alternative to current pharmacological immunosuppressive therapies. However, a more comprehensive understanding of their characteristics, isolation, activation, and expansion is needed to be able design cost effective therapies. Here, we review the practicalities of making Tregs a viable cell therapy, in particular, discussing the challenges faced in isolating and manufacturing Tregs and defining what are the most appropriate applications for this new therapy.

  11. Transplantation Tolerance Induction: Cell Therapies and Their Mechanisms

    OpenAIRE

    Scalea, Joseph R.; Tomita, Yusuke; Lindholm, Christopher R.; Burlingham, William

    2016-01-01

    Cell based therapies have been studied extensively in the context of transplantation tolerance induction. The most successful protocols have relied on transfusion of bone marrow prior to the transplantation of a renal allograft. However, it is not clear that stem cells found in bone marrow are required in order to render a transplant candidate immunologically tolerant. Accordingly, mesenchymal stem cells, regulatory myeloid cells, T regulatory cells, and other cell types, are being tested as ...

  12. Cytokine production and apoptosis among T cells from patients under treatment for Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Kemp, K; Akanmori, B D; Adabayeri, V

    2002-01-01

    of peripheral T cells during and after the period of antimalarial treatment. A high proportion of peripheral CD3+ cells had an activated phenotype at and shortly after time of admission (day 0) and initiation of therapy. This activation peaked around day 2, and at this time-point peripheral T cells from......Available evidence suggests that Plasmodium falciparum malaria causes activation and reallocation of T cells, and that these in vivo primed cells re-emerge into the periphery following drug therapy. Here we have examined the cytokine production capacity and susceptibility to programmed cell death...... the patients could be induced to produce cytokines at conditions of limited cytokine response in cells from healthy control donors. Activated CD8hi and TCR-gammadelta+ cells were the primary IFN-gamma producers, whereas CD4+ cells constituted an important source of TNF-alpha. The proportion of apoptotic T...

  13. Current perspectives on the use of ancillary materials for the manufacture of cellular therapies.

    Science.gov (United States)

    Solomon, Jennifer; Csontos, Lynn; Clarke, Dominic; Bonyhadi, Mark; Zylberberg, Claudia; McNiece, Ian; Kurtzberg, Joanne; Bell, Rosemarie; Deans, Robert

    2016-01-01

    Continued growth in the cell therapy industry and commercialization of cell therapies that successfully advance through clinical trials has led to increased awareness around the need for specialized and complex materials utilized in their manufacture. Ancillary materials (AMs) are components or reagents used during the manufacture of cell therapy products but are not intended to be part of the final products. Commonly, there are limitations in the availability of clinical-grade reagents used as AMs. Furthermore, AMs may affect the efficacy of the cell product and subsequent safety of the cell therapy for the patient. As such, AMs must be carefully selected and appropriately qualified during the cell therapy development process. However, the ongoing evolution of cell therapy research, limited number of clinical trials and registered cell therapy products results in the current absence of specific regulations governing the composition, compliance, and qualification of AMs often leads to confusion by suppliers and users in this field. Here we provide an overview and interpretation of the existing global framework surrounding AM use and investigate some common misunderstandings within the industry, with the aim of facilitating the appropriate selection and qualification of AMs. The key message we wish to emphasize is that in order to most effectively mitigate risk around cell therapy development and patient safety, users must work with their suppliers and regulators to qualify each AM to assess source, purity, identity, safety, and suitability in a given application. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. Strategies to improve homing of mesenchymal stem cells for greater efficacy in stem cell therapy.

    Science.gov (United States)

    Naderi-Meshkin, Hojjat; Bahrami, Ahmad Reza; Bidkhori, Hamid Reza; Mirahmadi, Mahdi; Ahmadiankia, Naghmeh

    2015-01-01

    Stem/progenitor cell-based therapeutic approach in clinical practice has been an elusive dream in medical sciences, and improvement of stem cell homing is one of major challenges in cell therapy programs. Stem/progenitor cells have a homing response to injured tissues/organs, mediated by interactions of chemokine receptors expressed on the cells and chemokines secreted by the injured tissue. For improvement of directed homing of the cells, many techniques have been developed either to engineer stem/progenitor cells with higher amount of chemokine receptors (stem cell-based strategies) or to modulate the target tissues to release higher level of the corresponding chemokines (target tissue-based strategies). This review discusses both of these strategies involved in the improvement of stem cell homing focusing on mesenchymal stem cells as most frequent studied model in cellular therapies. © 2014 International Federation for Cell Biology.

  15. Amniotic fluid stem cells: a promising therapeutic resource for cell-based regenerative therapy.

    Science.gov (United States)

    Antonucci, Ivana; Pantalone, Andrea; Tete, Stefano; Salini, Vincenzo; Borlongan, Cesar V; Hess, David; Stuppia, Liborio

    2012-01-01

    Stem cells have been proposed as a powerful tool in the treatment of several human diseases, both for their ability to represent a source of new cells to replace those lost due to tissue injuries or degenerative diseases, and for the ability of produce trophic molecules able to minimize damage and promote recovery in the injured tissue. Different cell types, such as embryonic, fetal or adult stem cells, human fetal tissues and genetically engineered cell lines, have been tested for their ability to replace damaged cells and to restore the tissue function after transplantation. Amniotic fluid -derived Stem cells (AFS) are considered a novel resource for cell transplantation therapy, due to their high renewal capacity, the "in vitro" expression of embryonic cell lineage markers, and the ability to differentiate in tissues derived from all the three embryonic layers. Moreover, AFS do not produce teratomas when transplanted into animals and are characterized by a low antigenicity, which could represent an advantage for cell transplantation or cell replacement therapy. The present review focuses on the biological features of AFS, and on their potential use in the treatment of pathological conditions such as ischemic brain injury and bone damages.

  16. Mesenchymal Stem Cell Therapy in Diabetes Mellitus: Progress and Challenges

    Directory of Open Access Journals (Sweden)

    Nagwa El-Badri

    2013-01-01

    Full Text Available Advanced type 2 diabetes mellitus is associated with significant morbidity and mortality due to cardiovascular, nervous, and renal complications. Attempts to cure diabetes mellitus using islet transplantation have been successful in providing a source for insulin secreting cells. However, limited donors, graft rejection, the need for continued immune suppression, and exhaustion of the donor cell pool prompted the search for a more sustained source of insulin secreting cells. Stem cell therapy is a promising alternative for islet transplantation in type 2 diabetic patients who fail to control hyperglycemia even with insulin injection. Autologous stem cell transplantation may provide the best outcome for those patients, since autologous cells are readily available and do not entail prolonged hospital stays or sustained immunotoxic therapy. Among autologous adult stem cells, mesenchymal stem cells (MSCs therapy has been applied with varying degrees of success in both animal models and in clinical trials. This review will focus on the advantages of MSCs over other types of stem cells and the possible mechanisms by which MSCs transplant restores normoglycemia in type 2 diabetic patients. Sources of MSCs including autologous cells from diabetic patients and the use of various differentiation protocols in relation to best transplant outcome will be discussed.

  17. Hospital-based proton linear accelerator for particle therapy and radioisotope production

    Science.gov (United States)

    Lennox, Arlene J.

    1991-05-01

    Taking advantage of recent advances in linear accelerator technology, it is possible for a hospital to use a 70 MeV proton linac for fast neutron therapy, boron neutron capture therapy, proton therapy for ocular melanomas, and production of radiopharmaceuticals. The linac can also inject protons into a synchrotron for proton therapy of deep-seated tumors. With 180 μA average current, a single linac can support all these applications. This paper presents a conceptual design for a medical proton linac, switchyard, treatment rooms, and isotope production rooms. Special requirements for each application are outlined and a layout for sharing beam among the applications is suggested.

  18. Scientific Production about the Adherence to Antiretroviral Therapy

    Directory of Open Access Journals (Sweden)

    Regina Célia De Oliveira

    2017-09-01

    Full Text Available Objective: To identify the elite of authors about the subject adherence to antiretroviral therapy; to identify the journals turned to publishing articles about adherence to antiretroviral therapy; and to identify and analyze the most commonly used words in abstracts of articles about adherence to antiretroviral therapy. Method: A bibliometric study conducted through the Scopus base. We used articles published between 1996 and 2014, after application of the eligibility criteria, there were composed the sample with 24 articles. The data were analyzed descriptively. Were used the laws of bibliometric (Lotka, Bradford and Zipf and the conceptual cloud map of words, through the program Cmap tools. Results: Lotka's Law identified the 5 authors more productive (46% of the total published. Bradford is impaired in this study. Concerning Zipf, 3 zones were determined, 31.47% of the words with in the first zone, 26.46% in the second and 42.06% in the third. In the conceptual map, the words/factors that positively and negatively influence adherence were emphasized, among them the need for more research in the health services. Conclusion: There are few publications about the accession to antiretroviral therapy, and the scientific production is in the process of maturation. One can infer that the theme researched is not yet an obsolete topic. It should be noted that the Bibliometric was a relevant statistic tool to generate information about the publications about the antiretroviral therapy. Descriptors: Antiretroviral Therapy, Highly Active; Medication Adherence; Bibliometric; HIV; Acquired Immunodeficiency Syndrome

  19. Radiation Therapy Induces Macrophages to Suppress T-Cell Responses Against Pancreatic Tumors in Mice.

    Science.gov (United States)

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-06-01

    The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages

  20. Regulation of stem cell therapies under attack in Europe: for whom the bell tolls

    Science.gov (United States)

    Bianco, Paolo; Barker, Roger; Brüstle, Oliver; Cattaneo, Elena; Clevers, Hans; Daley, George Q; De Luca, Michele; Goldstein, Lawrence; Lindvall, Olle; Mummery, Christine; Robey, Pamela G; Sattler de Sousa e Brito, Clara; Smith, Austin

    2013-01-01

    At the time of writing, the Italian Parliament is debating a new law that would make it legal to practice an unproven stem cell treatment in public hospitals. The treatment, offered by a private non-medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulations. This case raises multiple concerns, most prominently the urgent need to protect patients who are severely ill, exposed to significant risks, and vulnerable to exploitation. The scientific community must consider the context—social, financial, medical, legal—in which stem cell science is currently situated and the need for stringent regulation. Additional concerns are emerging. These emanate from the novel climate, created within science itself, and stem cell science in particular, by the currently prevailing model of ‘translational medicine'. Only rigorous science and rigorous regulation can ensure translation of science into effective therapies rather than into ineffective market products, and mark, at the same time, the sharp distinction between the striving for new therapies and the deceit of patients. PMID:23644381

  1. [Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

    Science.gov (United States)

    Ueki, H

    1987-11-01

    We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

  2. Function of miR-146a-5p in Tumor Cells As a Regulatory Switch between Cell Death and Angiogenesis: Macrophage Therapy Revisited

    Directory of Open Access Journals (Sweden)

    Elina Simanovich

    2018-01-01

    Full Text Available Tumors survive and progress by evading killing mechanisms of the immune system, and by generating a tumor microenvironment (TME that reprograms macrophages in situ to produce factors that support tumor growth, angiogenesis, and metastasis. We have previously shown that by blocking the translation of the enzyme inducible nitric oxide synthase (iNOS, miR-146a-5p inhibits nitric oxide (NO production in a mouse renal carcinoma cell line (RENCA, thereby endowing RENCA cells with resistance to macrophage-induced cell death. Here, we expand these findings to the mouse colon carcinoma CT26 cell line and demonstrate that neutralizing miR-146a-5p’s activity by transfecting both RENCA and CT26 cells with its antagomir restored iNOS expression and NO production and enhanced susceptibility to macrophage-induced cell death (by 48 and 25%, respectively, p < 0.001. Moreover, miR-146a-5p suppression simultaneously inhibited the expression of the pro-angiogenic protein EMMPRIN (threefolds, p < 0.001, leading to reduced MMP-9 and vascular endothelial growth factor secretion (twofolds and threefolds, respectively, p < 0.05, and reduced angiogenesis, as estimated by in vitro tube formation and scratch assays. When we injected tumors with pro-inflammatory-stimulated RAW 264.7 macrophages together with i.v. injection of the miR-146a-5p antagomir, we found inhibited tumor growth (sixfolds, p < 0.001 and angiogenesis (twofolds, p < 0.01, and increased apoptosis (twofolds, p < 0.01. This combination therapy increased nitrites and reduced TGFβ concentrations in tumor lysates, alleviated immune suppression, and allowed enhanced infiltration of cytotoxic CD8+ T cells. Thus, miR-146a-5p functions as a control switch between angiogenesis and cell death, and its neutralization can manipulate the crosstalk between tumor cells and macrophages and profoundly change the TME. This strategy can be therapeutically utilized in combination with the macrophage

  3. Metastasis Targeted Therapies in Renal Cell Cancer

    OpenAIRE

    K. Fehmi Narter; Bora Özveren

    2018-01-01

    Metastatic renal cell cancer is a malignant disease and its treatment has been not been described clearly yet. These patients are generally symptomatic and resistant to current treatment modalities. Radiotherapy, chemotherapy, and hormonal therapy are not curative in many of these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (immunotherapy or targeted molecules), and metastasectomy has been shown to be hopeful in prolonging the survival and improvi...

  4. A review on stem cell therapy for multiple sclerosis: special focus on human embryonic stem cells.

    Science.gov (United States)

    Shroff, Geeta

    2018-01-01

    Multiple sclerosis (MS), a complex disorder of the central nervous system (CNS), is characterized with axonal loss underlying long-term progressive disability. Currently available therapies for its management are able to slow down the progression but fail to treat it completely. Moreover, these therapies are associated with major CNS and cardiovascular adverse events, and prolonged use of these treatments may cause life-threatening diseases. Recent research has shown that cellular therapies hold a potential for CNS repair and may be able to provide protection from inflammatory damage caused after injury. Human embryonic stem cell (hESC) transplantation is one of the promising cell therapies; hESCs play an important role in remyelination and help in preventing demylenation of the axons. In this study, an overview of the current knowledge about the unique properties of hESC and their comparison with other cell therapies has been presented for the treatment of patients with MS.

  5. Standardization of Good Manufacturing Practice-compliant production of bone marrow-derived human mesenchymal stromal cells for immunotherapeutic applications.

    Science.gov (United States)

    Wuchter, Patrick; Bieback, Karen; Schrezenmeier, Hubert; Bornhäuser, Martin; Müller, Lutz P; Bönig, Halvard; Wagner, Wolfgang; Meisel, Roland; Pavel, Petra; Tonn, Torsten; Lang, Peter; Müller, Ingo; Renner, Matthias; Malcherek, Georg; Saffrich, Rainer; Buss, Eike C; Horn, Patrick; Rojewski, Markus; Schmitt, Anita; Ho, Anthony D; Sanzenbacher, Ralf; Schmitt, Michael

    2015-02-01

    Human mesenchymal stem or stromal cells (MSCs) represent a potential resource not only for regenerative medicine but also for immunomodulatory cell therapies. The application of different MSC culture protocols has significantly hampered the comparability of experimental and clinical data from different laboratories and has posed a major obstacle for multicenter clinical trials. Manufacturing of cell products for clinical application in the European Community must be conducted in compliance with Good Manufacturing Practice and requires a manufacturing license. In Germany, the Paul-Ehrlich-Institut as the Federal Authority for Vaccines and Biomedicines is critically involved in the approval process. This report summarizes a consensus meeting between researchers, clinicians and regulatory experts on standard quality requirements for MSC production. The strategy for quality control testing depends on the product's cell composition, the manufacturing process and the indication and target patient population. Important quality criteria in this sense are, among others, the immunophenotype of the cells, composition of the culture medium and the risk for malignant transformation, as well as aging and the immunosuppressive potential of the manufactured MSCs. This position paper intends to provide relevant information to interested parties regarding these criteria to foster the development of scientifically valid and harmonized quality standards and to support approval of MSC-based investigational medicinal products. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. Nano scaffolds and stem cell therapy in liver tissue engineering

    Science.gov (United States)

    Montaser, Laila M.; Fawzy, Sherin M.

    2015-08-01

    Tissue engineering and regenerative medicine have been constantly developing of late due to the major progress in cell and organ transplantation, as well as advances in materials science and engineering. Although stem cells hold great potential for the treatment of many injuries and degenerative diseases, several obstacles must be overcome before their therapeutic application can be realized. These include the development of advanced techniques to understand and control functions of micro environmental signals and novel methods to track and guide transplanted stem cells. A major complication encountered with stem cell therapies has been the failure of injected cells to engraft to target tissues. The application of nanotechnology to stem cell biology would be able to address those challenges. Combinations of stem cell therapy and nanotechnology in tissue engineering and regenerative medicine have achieved significant advances. These combinations allow nanotechnology to engineer scaffolds with various features to control stem cell fate decisions. Fabrication of Nano fiber cell scaffolds onto which stem cells can adhere and spread, forming a niche-like microenvironment which can guide stem cells to proceed to heal damaged tissues. In this paper, current and emergent approach based on stem cells in the field of liver tissue engineering is presented for specific application. The combination of stem cells and tissue engineering opens new perspectives in tissue regeneration for stem cell therapy because of the potential to control stem cell behavior with the physical and chemical characteristics of the engineered scaffold environment.

  7. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D.; Qayyum, Abbas A.

    2016-01-01

    ), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much...... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct...... location, timing and route of delivery, cell dosage, cell type etc. The present review will try to elaborate and clarify the present status for stem cell therapy in STEMI....

  8. Experimental myocardial stem cell therapy for ST-elevation myocardial infarction

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja D; Qayyum, Abbas A

    2016-01-01

    ), chronic IHD and heart failure. The patients suffer from chest pain (angina), dyspnea and a reduced quality of life. Common for all these conditions is loss of functional cardiomyocytes and endothelial cells. Stem cell therapy to regenerate injured myocardium is a new treatment option which has gained much...... location, timing and route of delivery, cell dosage, cell type etc. The present review will try to elaborate and clarify the present status for stem cell therapy in STEMI....... interest in the last 10-15 years especially after STEMI. Many preclinical and clinical studies have shown encouraging results but also very diverse clinical outcomes after stem cell treatment. This diversity in results may be explained by different factors, such as cell isolation technique, infarct...

  9. Recent advances in cell-based therapy for Parkinson disease

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Cooper, Oliver; Vinuela, Angel

    2008-01-01

    In this review, the authors discuss recent advances in the field of cell therapy for Parkinson disease (PD). They compare and contrast recent clinical trials using fetal dopaminergic neurons. They attribute differences in cell preparation techniques, cell type specification, and immunosuppression...

  10. Stem cells for amyotrophic lateral sclerosis modeling and therapy: myth or fact?

    Science.gov (United States)

    Coatti, G C; Beccari, M S; Olávio, T R; Mitne-Neto, M; Okamoto, O K; Zatz, M

    2015-03-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy. © 2015 International Society for Advancement of Cytometry.

  11. Good Manufacturing Practices (GMP) manufacturing of advanced therapy medicinal products: a novel tailored model for optimizing performance and estimating costs.

    Science.gov (United States)

    Abou-El-Enein, Mohamed; Römhild, Andy; Kaiser, Daniel; Beier, Carola; Bauer, Gerhard; Volk, Hans-Dieter; Reinke, Petra

    2013-03-01

    Advanced therapy medicinal products (ATMP) have gained considerable attention in academia due to their therapeutic potential. Good Manufacturing Practice (GMP) principles ensure the quality and sterility of manufacturing these products. We developed a model for estimating the manufacturing costs of cell therapy products and optimizing the performance of academic GMP-facilities. The "Clean-Room Technology Assessment Technique" (CTAT) was tested prospectively in the GMP facility of BCRT, Berlin, Germany, then retrospectively in the GMP facility of the University of California-Davis, California, USA. CTAT is a two-level model: level one identifies operational (core) processes and measures their fixed costs; level two identifies production (supporting) processes and measures their variable costs. The model comprises several tools to measure and optimize performance of these processes. Manufacturing costs were itemized using adjusted micro-costing system. CTAT identified GMP activities with strong correlation to the manufacturing process of cell-based products. Building best practice standards allowed for performance improvement and elimination of human errors. The model also demonstrated the unidirectional dependencies that may exist among the core GMP activities. When compared to traditional business models, the CTAT assessment resulted in a more accurate allocation of annual expenses. The estimated expenses were used to set a fee structure for both GMP facilities. A mathematical equation was also developed to provide the final product cost. CTAT can be a useful tool in estimating accurate costs for the ATMPs manufactured in an optimized GMP process. These estimates are useful when analyzing the cost-effectiveness of these novel interventions. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  12. Translating stem cell therapies: the role of companion animals in regenerative medicine

    OpenAIRE

    Volk, Susan W.; Theoret, Christine

    2013-01-01

    Veterinarians and veterinary medicine have been integral to the development of stem cell therapies. The contributions of large animal experimental models to the development and refinement of modern hematopoietic stem cell transplantation were noted nearly five decades ago. More recent advances in adult stem cell/regenerative cell therapies continue to expand knowledge of the basic biology and clinical applications of stem cells. A relatively liberal legal and ethical regulation of stem cell r...

  13. Generation of T cell effectors using tumor cell-loaded dendritic cells for adoptive T cell therapy

    Czech Academy of Sciences Publication Activity Database

    Vávrová, K.; Vrabcova, P.; Filipp, Dominik; Bartunkova, J.; Horváth, R.

    2016-01-01

    Roč. 33, č. 12 (2016), č. článku 136. ISSN 1357-0560 R&D Projects: GA ČR(CZ) GBP302/12/G101 Institutional support: RVO:68378050 Keywords : Cancer Immunotherapy * Prostate cancer * Adoptive T cell therapy * Tumor-specific T cell expansion Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.634, year: 2016

  14. Genetically modified T cells in cancer therapy: opportunities and challenges

    Directory of Open Access Journals (Sweden)

    Michaela Sharpe

    2015-04-01

    Full Text Available Tumours use many strategies to evade the host immune response, including downregulation or weak immunogenicity of target antigens and creation of an immune-suppressive tumour environment. T cells play a key role in cell-mediated immunity and, recently, strategies to genetically modify T cells either through altering the specificity of the T cell receptor (TCR or through introducing antibody-like recognition in chimeric antigen receptors (CARs have made substantial advances. The potential of these approaches has been demonstrated in particular by the successful use of genetically modified T cells to treat B cell haematological malignancies in clinical trials. This clinical success is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organisations. Although our understanding of the factors that influence the safety and efficacy of these therapies has increased, challenges for bringing genetically modified T-cell immunotherapy to many patients with different tumour types remain. These challenges range from the selection of antigen targets and dealing with regulatory and safety issues to successfully navigating the routes to commercial development. However, the encouraging clinical data, the progress in the scientific understanding of tumour immunology and the improvements in the manufacture of cell products are all advancing the clinical translation of these important cellular immunotherapies.

  15. Application of response surface methodology to maximize the productivity of scalable automated human embryonic stem cell manufacture.

    Science.gov (United States)

    Ratcliffe, Elizabeth; Hourd, Paul; Guijarro-Leach, Juan; Rayment, Erin; Williams, David J; Thomas, Robert J

    2013-01-01

    Commercial regenerative medicine will require large quantities of clinical-specification human cells. The cost and quality of manufacture is notoriously difficult to control due to highly complex processes with poorly defined tolerances. As a step to overcome this, we aimed to demonstrate the use of 'quality-by-design' tools to define the operating space for economic passage of a scalable human embryonic stem cell production method with minimal cell loss. Design of experiments response surface methodology was applied to generate empirical models to predict optimal operating conditions for a unit of manufacture of a previously developed automatable and scalable human embryonic stem cell production method. Two models were defined to predict cell yield and cell recovery rate postpassage, in terms of the predictor variables of media volume, cell seeding density, media exchange and length of passage. Predicted operating conditions for maximized productivity were successfully validated. Such 'quality-by-design' type approaches to process design and optimization will be essential to reduce the risk of product failure and patient harm, and to build regulatory confidence in cell therapy manufacturing processes.

  16. Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges.

    Science.gov (United States)

    Sneddon, Julie B; Tang, Qizhi; Stock, Peter; Bluestone, Jeffrey A; Roy, Shuvo; Desai, Tejal; Hebrok, Matthias

    2018-06-01

    Restoration of insulin independence and normoglycemia has been the overarching goal in diabetes research and therapy. While whole-organ and islet transplantation have become gold-standard procedures in achieving glucose control in diabetic patients, the profound lack of suitable donor tissues severely hampers the broad application of these therapies. Here, we describe current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation and present state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies. Copyright © 2018. Published by Elsevier Inc.

  17. GMP scale-up and banking of pluripotent stem cells for cellular therapy applications.

    Science.gov (United States)

    Ausubel, Lara J; Lopez, Patricia M; Couture, Larry A

    2011-01-01

    Human pluripotent stem cells (PSCs), which include human embryonic stem cells (ESCs) as well as induced pluripotent stem cells (iPSCs), represent an important source of cellular therapies in regenerative medicine and the study of early human development. As such, it is becoming increasingly important to develop methods for the large-scale banking of human PSC lines. There are several well-established methods for the propagation of human PSCs. The key to development of a good manufacturing practice (GMP) bank is to determine a manufacturing method that is amenable to large-scale production using materials that are fully documented. We have developed several banks of hESCs using animal feeder cells, animal-based matrices, or animal-free matrices. Protocols for growing hESCs on mouse embryonic fibroblasts (MEFs) are well established and are very helpful for producing research grade banks of cells. As most human ESCs cultured by research laboratories have been exposed to xenogeneic reagents, it is not imperative that all materials used in the production of a master cell bank be animal-free in origin. Nevertheless, as the field develops, it will no doubt become increasingly important to produce a bank of cells for clinical use without xenogeneic reagents, particularly nonhuman feeder cells which might harbor viruses with potential risk to human health or cell product integrity. Thus, even for cell lines previously exposed to xenogeneic reagents, it is important to minimize any subsequent exposure of the cell lines to additional adventitious agents. We have specifically described procedures for the growth of hESCs on Matrigel, an animal-matrix, and CELLstart, an animal-free matrix, and these can be used to produce hESCs as part of a clinical manufacturing process.

  18. Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies

    DEFF Research Database (Denmark)

    Gyöngyösi, Mariann; Wojakowski, Wojciech; Navarese, Eliano P

    2016-01-01

    In contrast to multiple publication-based meta-analyses involving clinical cardiac regeneration therapy in patients with recent myocardial infarction, a recently published meta-analysis based on individual patient data reported no effect of cell therapy on left ventricular function or clinical...

  19. Stem Cell-Based Therapies for Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Lei Hao

    2014-01-01

    Full Text Available In recent years, stem cell-based approaches have attracted more attention from scientists and clinicians due to their possible therapeutical effect on stroke. Animal studies have demonstrated that the beneficial effects of stem cells including embryonic stem cells (ESCs, inducible pluripotent stem cells (iPSCs, neural stem cells (NSCs, and mesenchymal stem cell (MSCs might be due to cell replacement, neuroprotection, endogenous neurogenesis, angiogenesis, and modulation on inflammation and immune response. Although several clinical studies have shown the high efficiency and safety of stem cell in stroke management, mainly MSCs, some issues regarding to cell homing, survival, tracking, safety, and optimal cell transplantation protocol, such as cell dose and time window, should be addressed. Undoubtably, stem cell-based gene therapy represents a novel potential therapeutic strategy for stroke in future.

  20. Improve T Cell Therapy in Neuroblastoma

    Science.gov (United States)

    2012-07-01

    Savoldo B, Vigouroux S et al. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte...Natl Acad Sci U S A. 2004;101(suppl 2):14622–14626. 8. Eghtesad S, Morel PA, Clemens PR. The companions : regulatory T cells and gene therapy...were euthanized and examined for NKT cell localiza- tion to the tumor tissues. Animals treated with anti-CCL2 or anti- CCL20 mAb had lower frequency

  1. CAR-T Cell Therapies From the Transfusion Medicine Perspective.

    Science.gov (United States)

    Fesnak, Andrew; Lin, ChieYu; Siegel, Don L; Maus, Marcela V

    2016-07-01

    The use of chimeric antigen receptor (CAR)-T cell therapy for the treatment of hematologic malignancies has generated significant excitement over the last several years. From a transfusion medicine perspective, the implementation of CAR-T therapy as a potential mainstay treatment for not only hematologic but also solid-organ malignancies represents a significant opportunity for growth and expansion. In this review, we will describe the rationale for the development of genetically redirected T cells as a cancer therapeutic, the different elements that are required to engineer these cells, as well as an overview of the process by which patient cells are harvested and processed to create and subsequently validate CAR-T cells. Finally, we will briefly describe some of the toxicities and clinical efficacy of CAR-T cells in the setting of patients with advanced malignancy. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Stem cell therapy for myocardial infarction

    NARCIS (Netherlands)

    A.D. Moelker (Amber)

    2007-01-01

    textabstractCoronary heart disease and heart failure continue to be significant burdens to healthcare systems in the Western world and are predicted to become so in emerging economies. Despite mixed results in both experimental and clinical studies, stem cell therapy is a promising option for

  3. Manufacturing Cell Therapies Using Engineered Biomaterials.

    Science.gov (United States)

    Abdeen, Amr A; Saha, Krishanu

    2017-10-01

    Emerging manufacturing processes to generate regenerative advanced therapies can involve extensive genomic and/or epigenomic manipulation of autologous or allogeneic cells. These cell engineering processes need to be carefully controlled and standardized to maximize safety and efficacy in clinical trials. Engineered biomaterials with smart and tunable properties offer an intriguing tool to provide or deliver cues to retain stemness, direct differentiation, promote reprogramming, manipulate the genome, or select functional phenotypes. This review discusses the use of engineered biomaterials to control human cell manufacturing. Future work exploiting engineered biomaterials has the potential to generate manufacturing processes that produce standardized cells with well-defined critical quality attributes appropriate for clinical testing. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies-the German Cancer Consortium approach.

    Science.gov (United States)

    Krackhardt, Angela M; Anliker, Brigitte; Hildebrandt, Martin; Bachmann, Michael; Eichmüller, Stefan B; Nettelbeck, Dirk M; Renner, Matthias; Uharek, Lutz; Willimsky, Gerald; Schmitt, Michael; Wels, Winfried S; Schüssler-Lenz, Martina

    2018-04-01

    Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

  5. Ambivalent journeys of hope: embryonic stem cell therapy in a clinic in India.

    Science.gov (United States)

    Prasad, Amit

    2015-03-01

    Stem cell therapy in non-Western countries such as India has received a lot of attention. Apart from media reports, there are a number of social science analyses of stem cell policy, therapy, and research, their ethical implications, and impact of advertising on patients. Nevertheless, in the media reports as well as in academic studies, experiences of patients, who undertake overseas journeys for stem cell therapy, have largely been either ignored or presented reductively, often as a "false hope." In this article, I analyze the experiences of patients and their "journeys of hope" to NuTech Mediworld, an embryonic stem cell therapy clinic in New Delhi, India. My analysis, which draws on my observations in the clinic and patients' experiences, instead of seeking to adjudicate whether embryonic stem cell therapy in clinics such as NuTech is right or wrong, true or false, focuses on how patients navigate and contest these concerns. I utilize Gilles Deleuze and Felix Guattari's "concepts," lines of flight and deterritorialization, to highlight how embryonic stem cell therapy's "political economy of hope" embodies deterritorialization of several "regimes of truth" and how these deterritorializations impact patients' experiences. © The Author(s) 2014.

  6. The Combination of Light and Stem Cell Therapies: A Novel Approach in Regenerative Medicine

    International Nuclear Information System (INIS)

    Anders, Juanita; Moges, Helina; Wu, Xingjia; Ilev, Ilko; Waynant, Ronald; Longo, Leonardo

    2010-01-01

    Light therapy commonly referred to as low level laser therapy can alter cellular functions and clinical conditions. Some of the commonly reported in vitro and in vivo effects of light therapy include cellular proliferation, alterations in the inflammatory response to injury, and increases in mitochondrial respiration and adenosine triphosphate synthesis. Based on the known effects of light on cells and tissues in general and on reports in the last 5 years on the interaction of light with stem cells, evidence is mounting indicating that light therapy could greatly benefit stem cell regenerative medicine. Experiments on a variety of harvested adult stem cells demonstrate that light therapy enhances differentiation and proliferation of the cells and alters the expression of growth factors in a number of different types of adult stem cells and progenitors in vitro. It also has the potential to attenuate cytotoxic effects of drugs used to purge harvested autologous stem cells and to increase survival of transplanted cells.

  7. [Regulatory requirements regarding cell-based medicinal products for human and veterinary use - a comparison].

    Science.gov (United States)

    Kuhlmann-Gottke, Johanna; Duchow, Karin

    2015-11-01

    At present, there is no separate regulatory framework for cell-based medicinal products (CBMP) for veterinary use at the European or German level. Current European and national regulations exclusively apply to the corresponding medicinal products for human use. An increasing number of requests for the regulatory classification of CBMP for veterinary use, such as allogeneic stem cell preparations and dendritic cell-based autologous tumour vaccines, and a rise in scientific advice for companies developing these products, illustrate the need for adequate legislation. Currently, advice is given and decisions are made on a case-by-case basis regarding the regulatory classification and authorisation requirements.Since some of the CBMP - in particular in the area of stem-cell products - are developed in parallel for human and veterinary use, there is an urgent need to create specific legal definitions, regulations, and guidelines for these complex innovative products in the veterinary sector as well. Otherwise, there is a risk that that the current legal grey area regarding veterinary medicinal products will impede therapeutic innovations in the long run. A harmonised EU-wide approach is desirable. Currently the European legislation on veterinary medicinal products is under revision. In this context, veterinary therapeutics based on allogeneic cells and tissues will be defined and regulated. Certainly, the legal framework does not have to be as comprehensive as for human CBMP; a leaner solution is conceivable, similar to the special provisions for advanced-therapy medicinal products laid down in the German Medicines Act.

  8. Challenges and prospects of chimeric antigen receptor T cell therapy in solid tumors.

    Science.gov (United States)

    Jindal, Vishal; Arora, Ena; Gupta, Sorab

    2018-05-05

    Chimeric antigen receptor (CAR) T cell therapy is a novel and innovative immunotherapy. CAR-T cells are genetically engineered T cells, carrying MHC independent specific antigen receptor and co-stimulatory molecule which can activate an immune response to a cancer specific antigen. This therapy showed great results in hematological malignancies but were unable to prove their worth in solid tumors. Likely reasons for their failure are lack of antigens, poor trafficking, and hostile tumor microenvironment. Excessive amount of research is going on to improve the efficacy of CAR T cell therapy in solid tumors. In this article, we will discuss the challenges faced in improving the outcome of CAR T cell therapy in solid tumors and various strategies adopted to curb them.

  9. 76 FR 9028 - Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability

    Science.gov (United States)

    2011-02-16

    ...] Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability AGENCY: Food and... Therapy Products'' dated January 2011. The guidance document provides manufacturers of cellular and gene... for Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance...

  10. Orchestration of transplantation tolerance by regulatory dendritic cell therapy or in situ targeting of dendritic cells

    Science.gov (United States)

    Morelli, Adrian E.; Thomson, Angus W.

    2014-01-01

    Purpose of review Extensive research in murine transplant models over the past two decades has convincingly demonstrated the ability of regulatory dendritic cells (DCreg) to promote long-term allograft survival. We review important considerations regarding the source of therapeutic DCreg (donor or recipient) and their mode of action, in situ targeting of DCreg, and optimal therapeutic regimens to promote DCreg function. Recent findings Recent studies have defined protocols and mechanisms whereby ex vivo-generated DCreg of donor or recipient origin subvert allogeneic T cell responses and promote long-term organ transplant survival. Particular interest has focused on how donor antigen (Ag) is acquired, processed and presented by autologous DCs, on the stability of DCreg, and on in situ targeting of DC to promote their tolerogenic function. New evidence of the therapeutic efficacy of DCreg in a clinically-relevant non-human primate organ transplant model and production of clinical grade DCreg support early evaluation of DCreg therapy in human graft recipients. Summary We discuss strategies currently used to promote DC tolerogenicity, including DCreg therapy and in situ targeting of DC, with a view to improved understanding of underlying mechanisms and identification of the most promising strategies for therapeutic application. PMID:24926700

  11. Structure-function Evaluation of Stem Cell Therapies for Spinal Cord Injury.

    Science.gov (United States)

    Zhang, Fuguo

    2018-02-23

    Spinal cord injuries (SCI) are prevalent, devastating for quality and expectancy of life, and cause heavy economic burdens. Stem cell therapies hold promise in complete structural and functional restoration of SCI. This review focuses on the methods currently used to evaluate the stem cell therapies for SCI. Various kinds of stem cells involving embryonic stem cells (ESCs), bone marrow stromal cells (BMSCs), neural stem cells (NSCs) and induced pluripotent stem cells (iPSCs) are extensively used in regenerative research of SCI. For evaluation, the survival and integration of transplanted cells, spinal cord reconstruction and functional recovery all should be considered. Histological and histochemistrical, microscopic, and colorimetric assays, and real-time RT-PCR techniques are applied to determine the outcome. From the three main aspects-transplanted cells, spinal cord structure, and functional recovery-we summarize and discuss these methods with certain instances of applications in SCI models. Importantly, for the evaluations of function, neuronal transmitting, electrophysiological analysis and behavioral score are included. Wider conjunction of established technologies, as well as the further development of nondestructive methods might make a big difference in testing stem cell therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Can the outcomes of mesenchymal stem cell-based therapy for myocardial infarction be improved? Providing weapons and armour to cells.

    Science.gov (United States)

    Karpov, Andrey A; Udalova, Daria V; Pliss, Michael G; Galagudza, Michael M

    2017-04-01

    Use of mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been found to have infarct-limiting effects in numerous experimental and clinical studies. However, recent meta-analyses of randomized clinical trials on MSC-based MI therapy have highlighted the need for improving its efficacy. There are two principal approaches for increasing therapeutic effect of MSCs: (i) preventing massive MSC death in ischaemic tissue and (ii) increasing production of cardioreparative growth factors and cytokines with transplanted MSCs. In this review, we aim to integrate our current understanding of genetic approaches that are used for modification of MSCs to enable their improved survival, engraftment, integration, proliferation and differentiation in the ischaemic heart. Genetic modification of MSCs resulting in increased secretion of paracrine factors has also been discussed. In addition, data on MSC preconditioning with physical, chemical and pharmacological factors prior to transplantation are summarized. MSC seeding on three-dimensional polymeric scaffolds facilitates formation of both intercellular connections and contacts between cells and the extracellular matrix, thereby enhancing cell viability and function. Use of genetic and non-genetic approaches to modify MSC function holds great promise for regenerative therapy of myocardial ischaemic injury. © 2016 John Wiley & Sons Ltd.

  13. Photothermal therapy of cancer cells using magnetic carbon nanoparticles

    Science.gov (United States)

    Vardarajan, V.; Gu, L.; Kanneganti, A.; Mohanty, S. K.; Koymen, A. R.

    2011-03-01

    Photothermal therapy offers a solution for the destruction of cancer cells without significant collateral damage to otherwise healthy cells. Several attempts are underway in using carbon nanoparticles (CNPs) and nanotubes due to their excellent absorption properties in the near-infrared spectrum of biological window. However, minimizing the required number of injected nanoparticles, to ensure minimal cytotoxicity, is a major challenge. We report on the introduction of magnetic carbon nanoparticles (MCNPs) onto cancer cells, localizing them in a desired region by applying an external magnetic field and irradiating them with a near-infrared laser beam. The MCNPs were prepared in Benzene, using an electric plasma discharge, generated in the cavitation field of an ultrasonic horn. The CNPs were made ferromagnetic by use of Fe-electrodes to dope the CNPs, as confirmed by magnetometry. Transmission electron microscopy measurements showed the size distribution of these MCNPs to be in the range of 5-10 nm. For photothermal irradiation, a tunable continuous wave Ti: Sapphire laser beam was weakly focused on to the cell monolayer under an inverted fluorescence microscope. The response of different cell types to photothermal irradiation was investigated. Cell death in the presence of both MCNPs and laser beam was confirmed by morphological changes and propidium iodide fluorescence inclusion assay. The results of our study suggest that MCNP based photothermal therapy is a promising approach to remotely guide photothermal therapy.

  14. Integration of genomics, proteomics, and imaging for cardiac stem cell therapy

    International Nuclear Information System (INIS)

    Chun, Hyung J.; Wilson, Kitch O.; Huang, Mei; Wu, Joseph C.

    2007-01-01

    Cardiac stem cell therapy is beginning to mature as a valid treatment for heart disease. As more clinical trials utilizing stem cells emerge, it is imperative to establish the mechanisms by which stem cells confer benefit in cardiac diseases. In this paper, we review three methods - molecular cellular imaging, gene expression profiling, and proteomic analysis - that can be integrated to provide further insights into the role of this emerging therapy. (orig.)

  15. Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology.

    Science.gov (United States)

    Gómez-Barrena, Enrique; Rosset, Philippe; Müller, Ingo; Giordano, Rosaria; Bunu, Carmen; Layrolle, Pierre; Konttinen, Yrjö T; Luyten, Frank P

    2011-06-01

    Regenerative medicine seeks to repair or replace damaged tissues or organs, with the goal to fully restore structure and function without the formation of scar tissue. Cell based therapies are promising new therapeutic approaches in regenerative medicine. By using mesenchymal stem cells, good results have been reported for bone engineering in a number of clinical studies, most of them investigator initiated trials with limited scope with respect to controls and outcome. With the implementation of a new regulatory framework for advanced therapeutic medicinal products, the stage is set to improve both the characterization of the cells and combination products, and pave the way for improved controlled and well-designed clinical trials. The incorporation of more personalized medicine approaches, including the use of biomarkers to identify the proper patients and the responders to treatment, will be contributing to progress in the field. Both translational and clinical research will move the boundaries in the field of regenerative medicine, and a coordinated effort will provide the clinical breakthroughs, particularly in the many applications of bone engineering. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  16. Bioprocessing automation in cell therapy manufacturing: Outcomes of special interest group automation workshop.

    Science.gov (United States)

    Ball, Oliver; Robinson, Sarah; Bure, Kim; Brindley, David A; Mccall, David

    2018-04-01

    Phacilitate held a Special Interest Group workshop event in Edinburgh, UK, in May 2017. The event brought together leading stakeholders in the cell therapy bioprocessing field to identify present and future challenges and propose potential solutions to automation in cell therapy bioprocessing. Here, we review and summarize discussions from the event. Deep biological understanding of a product, its mechanism of action and indication pathogenesis underpin many factors relating to bioprocessing and automation. To fully exploit the opportunities of bioprocess automation, therapeutics developers must closely consider whether an automation strategy is applicable, how to design an 'automatable' bioprocess and how to implement process modifications with minimal disruption. Major decisions around bioprocess automation strategy should involve all relevant stakeholders; communication between technical and business strategy decision-makers is of particular importance. Developers should leverage automation to implement in-process testing, in turn applicable to process optimization, quality assurance (QA)/ quality control (QC), batch failure control, adaptive manufacturing and regulatory demands, but a lack of precedent and technical opportunities can complicate such efforts. Sparse standardization across product characterization, hardware components and software platforms is perceived to complicate efforts to implement automation. The use of advanced algorithmic approaches such as machine learning may have application to bioprocess and supply chain optimization. Automation can substantially de-risk the wider supply chain, including tracking and traceability, cryopreservation and thawing and logistics. The regulatory implications of automation are currently unclear because few hardware options exist and novel solutions require case-by-case validation, but automation can present attractive regulatory incentives. Copyright © 2018 International Society for Cellular Therapy

  17. Stem cells therapy for ALS.

    Science.gov (United States)

    Mazzini, Letizia; Vescovi, Angelo; Cantello, Roberto; Gelati, Maurizio; Vercelli, Alessandro

    2016-01-01

    Despite knowledge on the molecular basis of amyotrophic lateral sclerosis (ALS) having quickly progressed over the last few years, such discoveries have not yet translated into new therapeutics. With the advancement of stem cell technologies there is hope for stem cell therapeutics as novel treatments for ALS. We discuss in detail the therapeutic potential of different types of stem cells in preclinical and clinical works. Moreover, we address many open questions in clinical translation. SC therapy is a potentially promising new treatment for ALS and the need to better understand how to develop cell-based experimental treatments, and how to implement them in clinical trials, becomes more pressing. Mesenchymal stem cells and neural fetal stem cells have emerged as safe and potentially effective cell types, but there is a need to carry out appropriately designed experimental studies to verify their long-term safety and possibly efficacy. Moreover, the cost-benefit analysis of the results must take into account the quality of life of the patients as a major end point. It is our opinion that a multicenter international clinical program aime d at fine-tuning and coordinating transplantation procedures and protocols is mandatory.

  18. Specifically targeted gene therapy for small-cell lung cancer

    DEFF Research Database (Denmark)

    Christensen, C.L.; Zandi, R.; Gjetting, T.

    2009-01-01

    Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous...

  19. Hydroxyurea therapy in adult Nigerian sickle cell disease: a ...

    African Journals Online (AJOL)

    Background: The clinical prospects of hydroxyurea therapy in the management of sickle cell disease (SCD) require evaluation in the Nigerian setting to develop indigenous guidelines. This survey examines the pattern of hydroxyurea therapy, its clinico-haematologic benefits and safety profile in Nigerian SCD subjects.

  20. Strategies to Maximize the Potential of Marine Biomaterials as a Platform for Cell Therapy

    Science.gov (United States)

    Kim, Hyeongmin; Lee, Jaehwi

    2016-01-01

    Marine biopolymers have been explored as a promising cell therapy system for efficient cell delivery and tissue engineering. However, the marine biomaterial-based systems themselves have exhibited limited performance in terms of maintenance of cell viability and functions, promotion of cell proliferation and differentiation as well as cell delivery efficiency. Thus, numerous novel strategies have been devised to improve cell therapy outcomes. The strategies include optimization of physical and biochemical properties, provision of stimuli-responsive functions, and design of platforms for efficient cell delivery and tissue engineering. These approaches have demonstrated substantial improvement of therapeutic outcomes in a variety of research settings. In this review, therefore, research progress made with marine biomaterials as a platform for cell therapy is reported along with current research directions to further advance cell therapies as a tool to cure incurable diseases. PMID:26821034

  1. Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation.

    Science.gov (United States)

    Ueda, Masumi; Berger, Melvin; Gale, Robert Peter; Lazarus, Hillard M

    2018-03-01

    Immunoglobulins are used to prevent or reduce infection risk in primary immune deficiencies and in settings which exploit its anti-inflammatory and immune-modulatory effects. Rigorous proof of immunoglobulin efficacy in persons with lympho-proliferative neoplasms, plasma cell myeloma, and persons receiving hematopoietic cell transplants is lacking despite many clinical trials. Further, there are few consensus guidelines or algorithms for use in these conditions. Rapid development of new therapies targeting B-cell signaling and survival pathways and increased use of chimeric antigen receptor T-cell (CAR-T) therapy will likely result in more acquired deficiencies of humoral immunity and infections in persons with cancer. We review immunoglobulin formulations and discuss efficacy and potential adverse effects in the context of preventing infections and in graft-versus-host disease. We suggest an algorithm for evaluating acquired deficiencies of humoral immunity in persons with hematologic neoplasms and recommend appropriate use of immunoglobulin therapy. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. T-cell responses targeting HIV Nef uniquely correlate with infected cell frequencies after long-term antiretroviral therapy.

    Directory of Open Access Journals (Sweden)

    Allison S Thomas

    2017-09-01

    Full Text Available HIV-specific CD8+ T-cell responses limit viral replication in untreated infection. After the initiation of antiretroviral therapy (ART, these responses decay and the infected cell population that remains is commonly considered to be invisible to T-cells. We hypothesized that HIV antigen recognition may persist in ART-treated individuals due to low-level or episodic protein expression. We posited that if persistent recognition were occurring it would be preferentially directed against the early HIV gene products Nef, Tat, and Rev as compared to late gene products, such as Gag, Pol, and Env, which have higher barriers to expression. Using a primary cell model of latency, we observed that a Nef-specific CD8+ T-cell clone exhibited low-level recognition of infected cells prior to reactivation and robust recognition shortly thereafter. A Gag-specific CD8+ T-cell clone failed to recognized infected cells under these conditions, corresponding with a lack of detectable Gag expression. We measured HIV-specific T-cell responses in 96 individuals who had been suppressed on ART for a median of 7 years, and observed a significant, direct correlation between cell-associated HIV DNA levels and magnitudes of IFN-γ-producing Nef/Tat/Rev-specific T-cell responses. This correlation was confirmed in an independent cohort (n = 18. Correlations were not detected between measures of HIV persistence and T-cell responses to other HIV antigens. The correlation with Nef/Tat/Rev-specific T-cells was attributable to Nef-specific responses, the breadth of which also correlated with HIV DNA levels. These results suggest that ongoing Nef expression in ART-treated individuals drives preferential maintenance and/or expansion of T-cells reactive to this protein, implying sensing of infected cells by the immune system. The direct correlation, however, suggests that recognition does not result in efficient elimination of infected cells. These results raise the possibility that

  3. Non-Cell Autonomous Effects of the Senescence-Associated Secretory Phenotype in Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Tareq Saleh

    2018-05-01

    Full Text Available In addition to promoting various forms of cell death, most conventional anti-tumor therapies also promote senescence. There is now extensive evidence that therapy-induced senescence (TIS might be transient, raising the concern that TIS could represent an undesirable outcome of therapy by providing a mechanism for tumor dormancy and eventual disease recurrence. The senescence-associated secretory phenotype (SASP is a hallmark of TIS and may contribute to aberrant effects of cancer therapy. Here, we propose that the SASP may also serve as a major driver of escape from senescence and the re-emergence of proliferating tumor cells, wherein factors secreted from the senescent cells contribute to the restoration of tumor growth in a non-cell autonomous fashion. Accordingly, anti-SASP therapies might serve to mitigate the deleterious outcomes of TIS. In addition to providing an overview of the putative actions of the SASP, we discuss recent efforts to identify and eliminate senescent tumor cells.

  4. Effect of 2 herbal intramammary products on milk quantity and quality compared with conventional and no dry cow therapy.

    Science.gov (United States)

    Mullen, K A E; Anderson, K L; Washburn, S P

    2014-01-01

    Dry cow therapy, administered at the end of lactation, is aimed at eliminating current and preventing future intramammary (IMM) bacterial infections and typically involves intramammary administration of antibiotics. Certified organic dairies in the United States are restricted from using antibiotics and must consider an alternative therapy or no dry cow therapy. The current study compared 2 herbal products to conventional dry cow therapy and no treatment for a total of 5 treatments over 2 trials. Trial 1 was conducted over 3 yr on 1 research farm and trial 2 included 4 commercial farms plus the research herd over 2 yr. Treatments included (1) a conventional IMM antibiotic and internal teat sealant (penicillin-dihydrostreptomycin and bismuth subnitrate; CON); (2) an herbal IMM product purported to act as a teat sealant (Cinnatube, New AgriTech Enterprises, Locke, NY; CIN); (3) an herbal IMM product (Phyto-Mast, Bovinity Health LLC, Narvon, PA; P-M); (4) Phyto-Mast and Cinnatube (PC); or (5) no dry cow therapy (NT). Each treatment group was balanced by breed, lactation number, due date, herd, and year. However, the CON treatment was used only in the research herd because of the intent to avoid antibiotic usage on the other 4 farms. Comparisons among treatments included the difference between pre- and posttreatment 305-d mature equivalent milk production (trial 1), somatic cell score change from dry-off to freshening at the cow and quarter levels (trials 1 and 2), and milk microbiology change over the dry period (trial 2). We detected no significant differences among treatments for milk yield differences between the lactation following treatment and the lactation preceding treatment. Changes in somatic cell score from one lactation to the next also did not differ significantly among treatments in either trial. Cure rates were not significantly different among treatments; only 19.6% of all quarters were infected at dry off. The proportion of quarters with new

  5. Workshop to address gaps in regulation of minimally manipulated autologous cell therapies for homologous use in Canada.

    Science.gov (United States)

    Chisholm, Jolene; von Tigerstrom, Barbara; Bedford, Patrick; Fradette, Julie; Viswanathan, Sowmya

    2017-12-01

    In Canada, minimally manipulated autologous cell therapies for homologous use (MMAC-H) are either regulated under the practice of medicine, or as drugs or devices under the Food and Drugs Act, Food and Drug Regulations (F&DR) or Medical Device Regulations (MDR). Cells, Tissues and Organs (CTO) Regulations in Canada are restricted to minimally manipulated allogeneic products for homologous use. This leaves an important gap in the interpretation of existing regulations. The purposes of this workshop co-organized by the Stem Cell Network and the Centre for Commercialization of Regenerative Medicine (CCRM) were to discuss the current state of regulation of MMAC-H therapies in Canada and compare it with other regulatory jurisdictions, with the intent of providing specific policy recommendations to Health Canada. Participants came to a consensus on the need for well-defined common terminology between regulators and stakeholders, a common source of confusion and misinformation. A need for a harmonized national approach to oversight of facilities providing MMAC-H therapies based on existing standards, such as Canadian Standards Association (CSA), was also voiced. Facilities providing MMAC-H therapies should also participate in collection of long-term data to ensure patient safety and efficacy of therapies. Harmonization across provinces of the procedures and practices involving administration of MMAC-H would be preferred. Participants felt that devices used to process MMAC-H are adequately regulated under existing MDR. Overly prescriptive regulation will stifle innovation, whereas insufficient regulation might allow unsafe or ineffective therapies to be offered. Until a clear, balanced and explicit approach is articulated, regulatory uncertainty remains a barrier. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. High dose therapy with autologous stem cell support in malignant disorders

    International Nuclear Information System (INIS)

    Holte, H.; Kvaloey, S.O.; Engan, T.

    1996-01-01

    New biomedical knowledge may improve the diagnostic procedures and treatment provided by the Health Services, but at additional cost. In a social democratic health care system, the hospital budgets have no room for expensive, new procedures or treatments, unless these are funded through extra allocation from the central authorities. High dose therapy with autologous stem cell support in malignant disorders is an example of a new and promising, but rather expensive treatment, but its role in cancer therapy has yet to be established. The indications for testing high dose therapy with autologous stem cell support in various malignancies are discussed, with emphasis on the principles for deciding which categories of disease should have priority. The authors suggest some malignant disorder for which high dose therapy with stem cell support should be explored versus conventional treatment in randomized prospective trials. 8 refs., 1 tab

  7. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    International Nuclear Information System (INIS)

    Pattani, Varun P.; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W.

    2015-01-01

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm 2 laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue

  8. Role of apoptosis and necrosis in cell death induced by nanoparticle-mediated photothermal therapy

    Energy Technology Data Exchange (ETDEWEB)

    Pattani, Varun P., E-mail: varun.pattani@utexas.edu; Shah, Jay; Atalis, Alexandra; Sharma, Anirudh; Tunnell, James W. [The University of Texas at Austin, Department of Biomedical Engineering (United States)

    2015-01-15

    Current cancer therapies can cause significant collateral damage due to a lack of specificity and sensitivity. Therefore, we explored the cell death pathway response to gold nanorod (GNR)-mediated photothermal therapy as a highly specific cancer therapeutic to understand the role of apoptosis and necrosis during intense localized heating. By developing this, we can optimize photothermal therapy to induce a maximum of ‘clean’ cell death pathways, namely apoptosis, thereby reducing external damage. GNRs were targeted to several subcellular localizations within colorectal tumor cells in vitro, and the cell death pathways were quantitatively analyzed after photothermal therapy using flow cytometry. In this study, we found that the cell death response to photothermal therapy was dependent on the GNR localization. Furthermore, we demonstrated that nanorods targeted to the perinuclear region irradiated at 37.5 W/cm{sup 2} laser fluence rate led to maximum cell destruction with the ‘cleaner’ method of apoptosis, at similar percentages as other anti-cancer targeted therapies. We believe that this indicates the therapeutic potential for GNR-mediated photothermal therapy to treat cancer effectively without causing damage to surrounding tissue.

  9. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

    Directory of Open Access Journals (Sweden)

    Shujing Shi

    Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

  10. Extinction models for cancer stem cell therapy

    Science.gov (United States)

    Sehl, Mary; Zhou, Hua; Sinsheimer, Janet S.; Lange, Kenneth L.

    2012-01-01

    Cells with stem cell-like properties are now viewed as initiating and sustaining many cancers. This suggests that cancer can be cured by driving these cancer stem cells to extinction. The problem with this strategy is that ordinary stem cells are apt to be killed in the process. This paper sets bounds on the killing differential (difference between death rates of cancer stem cells and normal stem cells) that must exist for the survival of an adequate number of normal stem cells. Our main tools are birth–death Markov chains in continuous time. In this framework, we investigate the extinction times of cancer stem cells and normal stem cells. Application of extreme value theory from mathematical statistics yields an accurate asymptotic distribution and corresponding moments for both extinction times. We compare these distributions for the two cell populations as a function of the killing rates. Perhaps a more telling comparison involves the number of normal stem cells NH at the extinction time of the cancer stem cells. Conditioning on the asymptotic time to extinction of the cancer stem cells allows us to calculate the asymptotic mean and variance of NH. The full distribution of NH can be retrieved by the finite Fourier transform and, in some parameter regimes, by an eigenfunction expansion. Finally, we discuss the impact of quiescence (the resting state) on stem cell dynamics. Quiescence can act as a sanctuary for cancer stem cells and imperils the proposed therapy. We approach the complication of quiescence via multitype branching process models and stochastic simulation. Improvements to the τ-leaping method of stochastic simulation make it a versatile tool in this context. We conclude that the proposed therapy must target quiescent cancer stem cells as well as actively dividing cancer stem cells. The current cancer models demonstrate the virtue of attacking the same quantitative questions from a variety of modeling, mathematical, and computational perspectives

  11. Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases.

    Science.gov (United States)

    Suen, Colin M; Mei, Shirley H J; Kugathasan, Lakshmi; Stewart, Duncan J

    2013-10-01

    Pulmonary arterial hypertension (PAH) is a devastating disease that, despite significant advances in medical therapies over the last several decades, continues to have an extremely poor prognosis. Gene therapy is a method to deliver therapeutic genes to replace defective or mutant genes or supplement existing cellular processes to modify disease. Over the last few decades, several viral and nonviral methods of gene therapy have been developed for preclinical PAH studies with varying degrees of efficacy. However, these gene delivery methods face challenges of immunogenicity, low transduction rates, and nonspecific targeting which have limited their translation to clinical studies. More recently, the emergence of regenerative approaches using stem and progenitor cells such as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) have offered a new approach to gene therapy. Cell-based gene therapy is an approach that augments the therapeutic potential of EPCs and MSCs and may deliver on the promise of reversal of established PAH. These new regenerative approaches have shown tremendous potential in preclinical studies; however, large, rigorously designed clinical studies will be necessary to evaluate clinical efficacy and safety. © 2013 American Physiological Society. Compr Physiol 3:1749-1779, 2013.

  12. Tensor Product of Polygonal Cell Complexes

    OpenAIRE

    Chien, Yu-Yen

    2017-01-01

    We introduce the tensor product of polygonal cell complexes, which interacts nicely with the tensor product of link graphs of complexes. We also develop the unique factorization property of polygonal cell complexes with respect to the tensor product, and study the symmetries of tensor products of polygonal cell complexes.

  13. Engineering a clinically-useful matrix for cell therapy.

    Science.gov (United States)

    Prestwich, Glenn D

    2008-01-01

    The design criteria for matrices for encapsulation of cells for cell therapy include chemical, biological, engineering, marketing, regulatory, and financial constraints. What is required is a biocompatible material for culture of cells in three-dimensions (3-D) that offers ease of use, experimental flexibility to alter composition and compliance, and a composition that would permit a seamless transition from in vitro to in vivo use. The challenge is to replicate the complexity of the native extracellular matrix (ECM) environment with the minimum number of components necessary to allow cells to rebuild a given tissue. Our approach is to deconstruct the ECM to a few modular components that can be reassembled into biomimetic materials that meet these criteria. These semi-synthetic ECMs (sECMs) employ thiol-modified derivatives of hyaluronic acid (HA) that can form covalently crosslinked, biodegradable hydrogels. These sECMs are "living" biopolymers, meaning that they can be crosslinked in the presence of cells or tissues to enable cell therapy and tissue engineering. Moreover, the sECMs allow inclusion of the appropriate biological cues needed to simulate the complexity of the ECM of a given tissue. Taken together, the sECM technology offers a manufacturable, highly reproducible, flexible, FDA-approvable, and affordable vehicle for cell expansion and differentiation in 3-D.

  14. Mounting of Biomaterials for Use in Ophthalmic Cell Therapies.

    Science.gov (United States)

    Harkin, Damien G; Dunphy, Siobhan E; Shadforth, Audra M A; Dawson, Rebecca A; Walshe, Jennifer; Zakaria, Nadia

    2017-11-01

    When used as scaffolds for cell therapies, biomaterials often present basic handling and logistical problems for scientists and surgeons alike. The quest for an appropriate mounting device for biomaterials is therefore a significant and common problem. In this review, we provide a detailed overview of the factors to consider when choosing an appropriate mounting device including those experienced during cell culture, quality assurance, and surgery. By way of example, we draw upon our combined experience in developing epithelial cell therapies for the treatment of eye diseases. We discuss commercially available options for achieving required goals and provide a detailed analysis of 4 experimental designs developed within our respective laboratories in Australia, the United Kingdom, and Belgium.

  15. CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis.

    Directory of Open Access Journals (Sweden)

    Alessandra Citro

    Full Text Available CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control. The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.

  16. Strategies for future histocompatible stem cell therapy

    DEFF Research Database (Denmark)

    Nehlin, Jan; Barington, Torben

    2009-01-01

    Stem cell therapy based on the safe and unlimited self-renewal of human pluripotent stem cells is envisioned for future use in tissue or organ replacement after injury or disease. A gradual decline of regenerative capacity has been documented among the adult stem cell population in some body organs...... during the aging process. Recent progress in human somatic cell nuclear transfer and inducible pluripotent stem cell technologies has shown that patient-derived nuclei or somatic cells can be reprogrammed in vitro to become pluripotent stem cells, from which the three germ layer lineages can be generated......, genetically identical to the recipient. Once differentiation protocols and culture conditions can be defined and optimized, patient-histocompatible pluripotent stem cells could be directed towards virtually every cell type in the human body. Harnessing this capability to enrich for given cells within...

  17. Improving the efficacy and safety of engineered T cell therapy for cancer.

    Science.gov (United States)

    Shi, Huan; Liu, Lin; Wang, Zhehai

    2013-01-28

    Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Myogenic Precursors from iPS Cells for Skeletal Muscle Cell Replacement Therapy

    Directory of Open Access Journals (Sweden)

    Isart Roca

    2015-01-01

    Full Text Available The use of adult myogenic stem cells as a cell therapy for skeletal muscle regeneration has been attempted for decades, with only moderate success. Myogenic progenitors (MP made from induced pluripotent stem cells (iPSCs are promising candidates for stem cell therapy to regenerate skeletal muscle since they allow allogenic transplantation, can be produced in large quantities, and, as compared to adult myoblasts, present more embryonic-like features and more proliferative capacity in vitro, which indicates a potential for more self-renewal and regenerative capacity in vivo. Different approaches have been described to make myogenic progenitors either by gene overexpression or by directed differentiation through culture conditions, and several myopathies have already been modeled using iPSC-MP. However, even though results in animal models have shown improvement from previous work with isolated adult myoblasts, major challenges regarding host response have to be addressed and clinically relevant transplantation protocols are lacking. Despite these challenges we are closer than we think to bringing iPSC-MP towards clinical use for treating human muscle disease and sporting injuries.

  19. Challenges and opportunities in the manufacture and expansion of cells for therapy.

    Science.gov (United States)

    Maartens, Joachim H; De-Juan-Pardo, Elena; Wunner, Felix M; Simula, Antonio; Voelcker, Nicolas H; Barry, Simon C; Hutmacher, Dietmar W

    2017-10-01

    Laboratory-based ex vivo cell culture methods are largely manual in their manufacturing processes. This makes it extremely difficult to meet regulatory requirements for process validation, quality control and reproducibility. Cell culture concepts with a translational focus need to embrace a more automated approach where cell yields are able to meet the quantitative production demands, the correct cell lineage and phenotype is readily confirmed and reagent usage has been optimized. Areas covered: This article discusses the obstacles inherent in classical laboratory-based methods, their concomitant impact on cost-of-goods and that a technology step change is required to facilitate translation from bed-to-bedside. Expert opinion: While traditional bioreactors have demonstrated limited success where adherent cells are used in combination with microcarriers, further process optimization will be required to find solutions for commercial-scale therapies. New cell culture technologies based on 3D-printed cell culture lattices with favourable surface to volume ratios have the potential to change the paradigm in industry. An integrated Quality-by-Design /System engineering approach will be essential to facilitate the scaled-up translation from proof-of-principle to clinical validation.

  20. From the Cover: Cell-replacement therapy for diabetes: Generating functional insulin-producing tissue from adult human liver cells

    Science.gov (United States)

    Sapir, Tamar; Shternhall, Keren; Meivar-Levy, Irit; Blumenfeld, Tamar; Cohen, Hamutal; Skutelsky, Ehud; Eventov-Friedman, Smadar; Barshack, Iris; Goldberg, Iris; Pri-Chen, Sarah; Ben-Dor, Lya; Polak-Charcon, Sylvie; Karasik, Avraham; Shimon, Ilan; Mor, Eytan; Ferber, Sarah

    2005-05-01

    Shortage in tissue availability from cadaver donors and the need for life-long immunosuppression severely restrict the large-scale application of cell-replacement therapy for diabetic patients. This study suggests the potential use of adult human liver as alternate tissue for autologous beta-cell-replacement therapy. By using pancreatic and duodenal homeobox gene 1 (PDX-1) and soluble factors, we induced a comprehensive developmental shift of adult human liver cells into functional insulin-producing cells. PDX-1-treated human liver cells express insulin, store it in defined granules, and secrete the hormone in a glucose-regulated manner. When transplanted under the renal capsule of diabetic, immunodeficient mice, the cells ameliorated hyperglycemia for prolonged periods of time. Inducing developmental redirection of adult liver offers the potential of a cell-replacement therapy for diabetics by allowing the patient to be the donor of his own insulin-producing tissue. pancreas | transdifferentiation

  1. Stem cell gene therapy for HIV: strategies to inhibit viral entry and replication.

    Science.gov (United States)

    DiGiusto, David L

    2015-03-01

    Since the demonstration of a cure of an HIV+ patient with an allogeneic stem cell transplant using naturally HIV-resistant cells, significant interest in creating similar autologous products has fueled the development of a variety of "cell engineering" approaches to stem cell therapy for HIV. Among the more well-studied strategies is the inhibition of viral entry through disruption of expression of viral co-receptors or through competitive inhibitors of viral fusion with the cell membrane. Preclinical evaluation of these approaches often starts in vitro but ultimately is tested in animal models prior to clinical implementation. In this review, we trace the development of several key approaches (meganucleases, short hairpin RNA (shRNA), and fusion inhibitors) to modification of hematopoietic stem cells designed to impart resistance to HIV to their T-cell and monocytic progeny. The basic evolution of technologies through in vitro and in vivo testing is discussed as well as the pros and cons of each approach and how the addition of postentry inhibitors may enhance the overall antiviral efficacy of these approaches.

  2. Rapid cell separation with minimal manipulation for autologous cell therapies

    Science.gov (United States)

    Smith, Alban J.; O'Rorke, Richard D.; Kale, Akshay; Rimsa, Roberts; Tomlinson, Matthew J.; Kirkham, Jennifer; Davies, A. Giles; Wälti, Christoph; Wood, Christopher D.

    2017-02-01

    The ability to isolate specific, viable cell populations from mixed ensembles with minimal manipulation and within intra-operative time would provide significant advantages for autologous, cell-based therapies in regenerative medicine. Current cell-enrichment technologies are either slow, lack specificity and/or require labelling. Thus a rapid, label-free separation technology that does not affect cell functionality, viability or phenotype is highly desirable. Here, we demonstrate separation of viable from non-viable human stromal cells using remote dielectrophoresis, in which an electric field is coupled into a microfluidic channel using shear-horizontal surface acoustic waves, producing an array of virtual electrodes within the channel. This allows high-throughput dielectrophoretic cell separation in high conductivity, physiological-like fluids, overcoming the limitations of conventional dielectrophoresis. We demonstrate viable/non-viable separation efficacy of >98% in pre-purified mesenchymal stromal cells, extracted from human dental pulp, with no adverse effects on cell viability, or on their subsequent osteogenic capabilities.

  3. Imaging: Guiding the Clinical Translation of Cardiac Stem Cell Therapy

    Science.gov (United States)

    Nguyen, Patricia K.; Lan, Feng; Wang, Yongming; Wu, Joseph C.

    2011-01-01

    Stem cells have been touted as the holy grail of medical therapy with promises to regenerate cardiac tissue, but it appears the jury is still out on this novel therapy. Using advanced imaging technology, scientists have discovered that these cells do not survive nor engraft long-term. In addition, only marginal benefit has been observed in large animal studies and human trials. However, all is not lost. Further application of advanced imaging technology will help scientists unravel the mysteries of stem cell therapy and address the clinical hurdles facing its routine implementation. In this review, we will discuss how advanced imaging technology will help investigators better define the optimal delivery method, improve survival and engraftment, and evaluate efficacy and safety. Insights gained from this review may direct the development of future preclinical investigations and clinical trials. PMID:21960727

  4. Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe

    Directory of Open Access Journals (Sweden)

    Andreas M. Farkas

    2017-05-01

    Full Text Available In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs. We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation. Prior to its introduction in 2008, 4.5% of the products submitted for orphan designation met these criteria. This percentage went up to 15% after 2008. We analyzed several parameters associated with active ATMP ODDs focusing on sponsor type and EU-Member State origin, therapeutic area targeted, and ATMP classification [i.e., somatic cell therapy medicinal product, tissue-engineered product (TEP, or gene therapy medicinal product (GTMP] and the use of regulatory services linked to incentives such as the use of protocol assistance (PA and other Committees [Committee for Advanced Therapies (CAT and the Pediatric Committee]. The aim here was to gain insight on the use of different services. The UK submits the largest number of ATMPs for ODD representing ~30% of the total to date. Few submissions have been received from central and Eastern European Member States as well as some of the larger Member States such as Germany (3.6%. ATMPs ODDs were primarily GTMPs (48.7% and SCTMPs (43.3%. TEPs only represented 8% of all submissions for this medicinal class. This is different from non-ODDs ATMPs where GTMPs make only 20% of ATMPs. A total of 11.7% of ATMP ODDs had received formal CAT classification. A total of 29.8% of all orphan drug (OD ATMPs requested PA. A total of 71.8% did not have an agreed pediatric investigation plan (PIP. Four products (Glybera one PA; Zalmoxis two; Holoclar one; Strimvelis three have received a marketing authorization (MAA and a 10-year market exclusivity. Strimvelis also completed their

  5. Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe.

    Science.gov (United States)

    Farkas, Andreas M; Mariz, Segundo; Stoyanova-Beninska, Violeta; Celis, Patrick; Vamvakas, Spiros; Larsson, Kristina; Sepodes, Bruno

    2017-01-01

    In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs). We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation. Prior to its introduction in 2008, 4.5% of the products submitted for orphan designation met these criteria. This percentage went up to 15% after 2008. We analyzed several parameters associated with active ATMP ODDs focusing on sponsor type and EU-Member State origin, therapeutic area targeted, and ATMP classification [i.e., somatic cell therapy medicinal product, tissue-engineered product (TEP), or gene therapy medicinal product (GTMP)] and the use of regulatory services linked to incentives such as the use of protocol assistance (PA) and other Committees [Committee for Advanced Therapies (CAT) and the Pediatric Committee]. The aim here was to gain insight on the use of different services. The UK submits the largest number of ATMPs for ODD representing ~30% of the total to date. Few submissions have been received from central and Eastern European Member States as well as some of the larger Member States such as Germany (3.6%). ATMPs ODDs were primarily GTMPs (48.7%) and SCTMPs (43.3%). TEPs only represented 8% of all submissions for this medicinal class. This is different from non-ODDs ATMPs where GTMPs make only 20% of ATMPs. A total of 11.7% of ATMP ODDs had received formal CAT classification. A total of 29.8% of all orphan drug (OD) ATMPs requested PA. A total of 71.8% did not have an agreed pediatric investigation plan (PIP). Four products (Glybera one PA; Zalmoxis two; Holoclar one; Strimvelis three) have received a marketing authorization (MAA) and a 10-year market exclusivity. Strimvelis also completed their PIP

  6. Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

    Science.gov (United States)

    Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

    2012-01-01

    X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

  7. Cell and Gene Therapies: European View on Challenges in Translation and How to Address Them

    Directory of Open Access Journals (Sweden)

    Cécile F. Rousseau

    2018-05-01

    Full Text Available Advanced therapy medicinal products (ATMPs, i.e., cell and gene therapy products, is a rapidly evolving field of therapeutic development. A significant proportion of the products are being developed by academia or small/medium-sized enterprises (SMEs. The many challenges in translation posed by this class of products include aspects covering: manufacturing, non-clinical development plan as relevant to clinical trial, marketing authorization, and reimbursement. In this context, the term translation refers to the relevance of non-clinical data in relation to how it impacts on appropriate and efficient clinical development. In order to successfully overcome these challenges, a clear understanding of the requirements and expectations of all the stakeholders is critical. This article aims to cover the potential challenges related to such translation and suggested approaches to find solutions based on experience and learnings from the perspective of European Union. While commercial challenges have a significant impact on the ATMPs in general, it is considered outside the scope of this article. However, by adopting a strong scientific basis for translation as suggested in this article, it is likely such an approach would help rather than harm successful real world clinical use of ATMPs.

  8. Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations

    Directory of Open Access Journals (Sweden)

    Seo-Young Lee

    2016-01-01

    Full Text Available The recent advent of induced pluripotent stem cells (iPSCs and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson’s disease, it has been well known that induced neural stem cells (iNSCs were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S. Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S, it would be ideal to simultaneously treat the LRRK2 (G2019S fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.

  9. Mesenchymal Stem Cell Based Therapy for Prostate Cancer

    Science.gov (United States)

    2015-11-01

    Montero-Menei, C.; Menei, P. Mesenchymal Stem Cells as Cellular Vehicles for Delivery of Nanoparticles to Brain Tumors. Biomaterials 2010, 31, 8393... Stem Cells : Considerations for Regenerative Medicine Approaches. Tissue Eng. Part B. Rev. 2010, 16, 159–168. 55. Ellem, S. J.; Taylor, R. a.; Furic, L...Award Number: W81XWH-13-1-0304 TITLE: Mesenchymal Stem Cell -Based Therapy for Prostate Cancer PRINCIPAL INVESTIGATOR: John Isaacs CONTRACTING

  10. Immune-based Therapies for Non-small Cell Lung Cancer.

    Science.gov (United States)

    Rafei, Hind; El-Bahesh, Ehab; Finianos, Antoine; Nassereddine, Samah; Tabbara, Imad

    2017-02-01

    Lung cancer is the leading cause of cancer-related death worldwide. Treatment of non-small cell lung cancer has evolved tremendously over the past decade. Specifically, immune checkpoint inhibitors have become an increasingly interesting target of pharmacological blockade. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination with other therapies. Vaccination in non-small cell lung cancer is also an emerging field of research that holds promising results for the future of immunotherapy in non-small cell lung cancer. This review presents a concise update on the most recent data regarding the role of checkpoint inhibitors as well as vaccination in non-small cell lung cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

    Science.gov (United States)

    Villaruz, Liza C.; Burns, Timothy F.; Ramfidis, Vasilis S.; Socinski, Mark A.

    2016-01-01

    The recognition that non–small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape of NSCLC to a personalized approach. This personalization of NSCLC therapy is typified by the dramatic response rates seen in EGFR mutant NSCLC when treated with targeted tyrosine kinase inhibitor therapy and in ALK translocation–driven NSCLC when treated with ALK inhibitors. Targeted therapeutic approaches in NSCLC necessitate consideration of more invasive biopsy techniques aimed at providing sufficient tissue for both histological determination and molecular profiling in all patients with stage IV disease both at the time of diagnosis and at the time of disease progression. Comprehensive genotyping efforts have identified oncogenic drivers in 62% lung adenocarcinomas and an increasing proportion of squamous cell carcinomas of the lung. The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer therapy where each genotype has an associated targeted therapy. This review outlines the state of personalized lung cancer therapy as it pertains to individual NSCLC genotypes. PMID:24258572

  12. Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

    Directory of Open Access Journals (Sweden)

    Irina V. Kholodenko

    2017-01-01

    Full Text Available The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.

  13. Translational research on advanced therapies

    Directory of Open Access Journals (Sweden)

    Filippo Belardelli

    2011-01-01

    Full Text Available Fostering translational research of advanced therapies has become a major priority of both scientific community and national governments. Advanced therapy medicinal products (ATMP are a new medicinal product category comprising gene therapy and cell-based medicinal products as well as tissue engineered medicinal products. ATMP development opens novel avenues for therapeutic approaches in numerous diseases, including cancer and neurodegenerative and cardiovascular diseases. However, there are important bottlenecks for their development due to the complexity of the regulatory framework, the high costs and the needs for good manufacturing practice (GMP facilities and new end-points for clinical experimentation. Thus, a strategic cooperation between different stakeholders (academia, industry and experts in regulatory issues is strongly needed. Recently, a great importance has been given to research infrastructures dedicated to foster translational medicine of advanced therapies. Some ongoing European initiatives in this field are presented and their potential impact is discussed.

  14. Translational research on advanced therapies.

    Science.gov (United States)

    Belardelli, Filippo; Rizza, Paola; Moretti, Franca; Carella, Cintia; Galli, Maria Cristina; Migliaccio, Giovanni

    2011-01-01

    Fostering translational research of advanced therapies has become a major priority of both scientific community and national governments. Advanced therapy medicinal products (ATMP) are a new medicinal product category comprising gene therapy and cell-based medicinal products as well as tissue engineered medicinal products. ATMP development opens novel avenues for therapeutic approaches in numerous diseases, including cancer and neurodegenerative and cardiovascular diseases. However, there are important bottlenecks for their development due to the complexity of the regulatory framework, the high costs and the needs for good manufacturing practice (GMP) facilities and new end-points for clinical experimentation. Thus, a strategic cooperation between different stakeholders (academia, industry and experts in regulatory issues) is strongly needed. Recently, a great importance has been given to research infrastructures dedicated to foster translational medicine of advanced therapies. Some ongoing European initiatives in this field are presented and their potential impact is discussed.

  15. Glucosamine-Based Supramolecular Nanotubes for Human Mesenchymal Cell Therapy.

    Science.gov (United States)

    Talloj, Satish Kumar; Cheng, Bill; Weng, Jen-Po; Lin, Hsin-Chieh

    2018-04-23

    Herein, we demonstrate an example of glucosamine-based supramolecular hydrogels that can be used for human mesenchymal cell therapy. We designed and synthesized a series of amino acid derivatives based on a strategy of capping d-glucosamine moiety at the C-terminus and fluorinated benzyl group at the N-terminus. From a systematic study on chemical structures, we discovered that the glucosamine-based supramolecular hydrogel [pentafluorobenzyl (PFB)-F-Glu] self-assembled with one-dimensional nanotubular structures at physiological pH. The self-assembly of a newly discovered PFB-F-Glu motif is attributed to the synergistic effect of π-π stacking and extensive intermolecular hydrogen bonding network in aqueous medium. Notably, PFB-F-Glu nanotubes are proven to be nontoxic to human mesenchymal stem cells (hMSCs) and have been shown to enhance hMSC proliferation while maintaining their pluripotency. Retaining of pluripotency capabilities provides potentially unlimited source of undifferentiated cells for the treatment of future cell therapies. Furthermore, hMSCs cultured on PFB-F-Glu are able to secrete paracrine factors that downregulate profibrotic gene expression in lipopolysaccharide-treated human skin fibroblasts, which demonstrates that PFB-F-Glu nanotubes have the potential to be used for wound healing applications. Overall, this article addresses the importance of chemical design to generate supramolecular biomaterials for stem cell therapy.

  16. Mesenchymal stem cell therapy for laryngotracheal stenosis

    DEFF Research Database (Denmark)

    Jakobsen, Kathrine Kronberg; Grønhøj, Christian; Jensen, David H

    2017-01-01

    BACKGROUND: Laryngotracheal stenosis (LTS) can be either congenital or acquired. Laryngeal stenosis is most often encountered after prolonged intubation. The mechanism for stenosis following intubation is believed to be hypertrophic scarring. Mesenchymal stem cells (MSCs) therapy has shown...

  17. Therapy effects of gold nanorods on the CNE-1 nasopharyngeal carcinoma cell line

    Directory of Open Access Journals (Sweden)

    Shao J

    2012-10-01

    Full Text Available Jinyan Shao,1 Jianguo Tang,1 Jian Ji,2 Wenbo Zhou21Department of Otolaryngology, Head and Neck Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 2Department of Polymer Science, Ministry of Education Key Laboratory of Macromolecule Synthesis and Functionalization, Zhejiang University, Hangzhou, People's Republic of ChinaAbstract: The use of nanocarriers to deliver drugs to tumor tissue is one of the most important strategies in cancer therapeutics. Recently, gold nanorods (GNRs have begun to be used in cancer therapy because of their unique properties. The purpose of this study was to show the potential that GNRs have against human nasopharyngeal carcinoma CNE-1 cells, using near-infrared (NIR laser light. Transmission electron microscopic and ultraviolet-visible spectroscopic investigations confirmed the efficient uptake of the GNRs by CNE-1 and human rhinal epithelia cells. The in vitro NIR photothermal therapy for the CNE-1 and rhinal epithelia cells was designed in three groups: (1 control, (2 laser alone, and (3 GNRs with laser. Fluorescence microscopy images indicated that, at some GNR concentrations and some intensities of NIR laser, GNRs with laser therapy could induce cell death for CNE-1 cells while keeping the rhinal epithelia cells healthy. Therefore, the results of this study suggest that using GNRs with NIR laser therapy can selectively destruct CNE-1 cells while having no effect on normal (rhinal epithelia cells.Keywords: photothermal therapy, near-infrared laser, rhinal epithelia cells, cell uptake

  18. Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

    International Nuclear Information System (INIS)

    Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

    2013-01-01

    Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma

  19. [Proangiogenic cell-based therapy for treatment of ischemic diseases].

    Science.gov (United States)

    Silvestre, Jean-Sébastien

    2009-11-01

    The application of endothelial progenitor cells (EPC) cell-based therapy for regenerative medicine constitutes a promising therapeutic avenue for the treatment of cardiovascular diseases. Based on experimental studies demonstrating that bone marrow-, blood- or tissue-derived stem/progenitor cells improve the functional recovery after ischemia, clinical trials were initiated to address this new therapeutic concept. Although autolougous cell therapy was shown to improve perfusion and function of ischemic tissues, a number of issues remain to be adressed. The nature of the mobilizing, migratory and homing signals, and the mechanisms of action need to be identified and further defined. In addition, strategies to enhance homing, survival and therapeutic potential of EPC need to be developped to improve therapeutic effect and counteract EPC dysfunction in aged patients with cardiovascular risk factors. The present review article will discuss the mechanisms of action of different types of adult stem cells and several approaches to improve their therapeutic efficiency.

  20. Antifibrotic Therapy in Simian Immunodeficiency Virus Infection Preserves CD4+ T-Cell Populations and Improves Immune Reconstitution With Antiretroviral Therapy

    Science.gov (United States)

    Estes, Jacob D.; Reilly, Cavan; Trubey, Charles M.; Fletcher, Courtney V.; Cory, Theodore J.; Piatak, Michael; Russ, Samuel; Anderson, Jodi; Reimann, Thomas G.; Star, Robert; Smith, Anthony; Tracy, Russell P.; Berglund, Anna; Schmidt, Thomas; Coalter, Vicky; Chertova, Elena; Smedley, Jeremy; Haase, Ashley T.; Lifson, Jeffrey D.; Schacker, Timothy W.

    2015-01-01

    Even with prolonged antiretroviral therapy (ART), many human immunodeficiency virus-infected individuals have <500 CD4+ T cells/µL, and CD4+ T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T-cell zone (TZ) that impairs homeostatic mechanisms required for T-cell survival. We therefore used antifibrotic therapy in simian immunodeficiency virus-infected rhesus macaques to determine whether decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4+ T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4+ T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4+ T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution. PMID:25246534

  1. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    Science.gov (United States)

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID:22530882

  2. PET molecular imaging in stem cell therapy for neurological diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiachuan; Zhang, Hong [Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Nuclear Medicine, Hangzhou, Zhejiang (China); Zhejiang University, Medical PET Center, Hangzhou (China); Institute of Nuclear Medicine and Molecular Imaging of Zhejiang University, Hangzhou (China); Key Laboratory of Medical Molecular Imaging of Zhejiang Province, Hangzhou (China); Tian, Mei [University of Texas, M.D. Anderson Cancer Center, Department of Experimental Diagnostic Imaging, Houston, TX (United States)

    2011-10-15

    Human neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal cord injury and multiple sclerosis are caused by loss of different types of neurons and glial cells in the brain and spinal cord. At present, there are no effective therapies against these disorders. Discovery of the therapeutic potential of stem cells offers new strategies for the treatment of neurological diseases. Direct assessment of stem cells' survival, interaction with the host and impact on neuronal functions after transplantation requires advanced in vivo imaging techniques. Positron emission tomography (PET) is a potential molecular imaging modality to evaluate the viability and function of transplanted tissue or stem cells in the nervous system. This review focuses on PET molecular imaging in stem cell therapy for neurological diseases. (orig.)

  3. Modified T-cells (using TCR and CTAs, chimeric antigen receptor (CAR and other molecular tools in recent gene therapy

    Directory of Open Access Journals (Sweden)

    A.S. Odiba

    2018-07-01

    Full Text Available T-cell-based cancer immunotherapy by the transfer of cloned TCRs that are isolated from tumor penetrating T-cells becomes a possibility through NY-ESOc259; a human-derived affinity-enhanced TCR that provides a level of sufficiency in long-term safety and efficacy. NY-ESOc259 recognizes a peptide common to CTAs (LAGE-1 and NY-ESO-1 in melanoma. Risks associated with insertion related transformation in gene therapy have been alleviated through strategies that include the engineering of transcription activator like effector nucleases (TALEN, RNA-guided nucleases (CRISPR/Cas9, Zinc-finger nucleases (ZFN. Cancer immunotherapy based on the genetic modification of autologous T-cells (dependent on the engineered autologous CD8+ T-cells, designed to distinguish and destroy cells bearing tumor-specific antigens via a CAR is able to exterminate B-cell leukemias and lymphomas that are resilient to conventional therapies. A tool with a very large reservoir of potentials in molecular therapy strategy is the Pluripotent Stem Cells (PSC, with pluripotency factors that include Klf4, Sox2, c-Myc, Oct4, differentiating into disease-associated cell phenotypes of three germ layers, comprising of mesoderm (e.g. cardiac cells, blood and muscle, endoderm (liver, pancreas and ectoderm (epidermis, neurons. It finds good application in disease modelling as well as therapeutic options in the restoration of CGD by using AAVS1 as the vector where the therapeutic cassette is integrated into the locus to restore superoxide production in the granulocytes. Fascinatingly, Clinical trial involving iPSC are already underway where scientists have plans to use iPSC-derived cells to treat macular degeneration (a devastating age-related eye disease. Application of these findings has redefined incurable diseases disorders as curable. Keywords: Clinical trials, Disorders, Gene therapy, Molecular biology, Pharmacotherapy, Vector

  4. Stem cell therapy: the great promise in lung disease.

    Science.gov (United States)

    Siniscalco, Dario; Sullo, Nikol; Maione, Sabatino; Rossi, Francesco; D'Agostino, Bruno

    2008-06-01

    Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.

  5. Gene therapy for sickle cell disease: An update.

    Science.gov (United States)

    Demirci, Selami; Uchida, Naoya; Tisdale, John F

    2018-05-30

    Sickle cell disease (SCD) is one of the most common life-threatening monogenic diseases affecting millions of people worldwide. Allogenic hematopietic stem cell transplantation is the only known cure for the disease with high success rates, but the limited availability of matched sibling donors and the high risk of transplantation-related side effects force the scientific community to envision additional therapies. Ex vivo gene therapy through globin gene addition has been investigated extensively and is currently being tested in clinical trials that have begun reporting encouraging data. Recent improvements in our understanding of the molecular pathways controlling mammalian erythropoiesis and globin switching offer new and exciting therapeutic options. Rapid and substantial advances in genome engineering tools, particularly CRISPR/Cas9, have raised the possibility of genetic correction in induced pluripotent stem cells as well as patient-derived hematopoietic stem and progenitor cells. However, these techniques are still in their infancy, and safety/efficacy issues remain that must be addressed before translating these promising techniques into clinical practice. Published by Elsevier Inc.

  6. Rethinking the role of myeloid-derived suppressor cells in adoptive T-cell therapy for cancer

    Science.gov (United States)

    Arina, Ainhoa

    2014-01-01

    The expansion of cancer-induced myeloid cells is thought to be one of the main obstacles to successful immunotherapy. Nevertheless, in murine tumors undergoing immune-mediated destruction by adoptively transferred T cells, we have recently shown that such cells maintain their immunosuppressive properties. Therefore, adoptive T-cell therapy can, under certain conditions, overcome myeloid cell immunosuppression. PMID:25050213

  7. 75 FR 54351 - Cell and Gene Therapy Clinical Trials in Pediatric Populations; Public Workshop

    Science.gov (United States)

    2010-09-07

    ...] Cell and Gene Therapy Clinical Trials in Pediatric Populations; Public Workshop AGENCY: Food and Drug... Biologics Evaluation and Research (CBER) is announcing a public workshop entitled ``Cell and Gene Therapy... Institutional Review Boards (IRBs), gene and cellular therapy clinical researchers, and other stakeholders...

  8. Rethinking on ethics and regulations in cell therapy as part of neurorestoratology

    Directory of Open Access Journals (Sweden)

    Sharma A

    2016-01-01

    Full Text Available Alok Sharma,1,2 Ziad M Al Zoubi3 1Department of Neurosurgery, Lokmanya Tilak Municipal General (LTMG Hospital and LTM Medical College, Mumbai, India; 2NeuroGen Brain and Spine Institute, Mumbai, India; 3Jordan Orthopedic and Spinal Centre, Amman, Jordan Abstract: Ethics, regulations, and evidence-based practices form the foundation of modern medicine. However, in recent years, and particularly in reference to cellular therapy, they have become obstacles to the growth and development of this new form of treatment. Based on four important documents, it is proposed that regulatory bodies and medical associations recommend an alternate way of looking at regulations for cell therapy, so as to ensure that only safe and effective treatments are offered to patients, and that greater availability of these new treatment options is also encouraged. The four documents on which these recommendations are based are: 1 World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects; 2 The International Society for Cellular Therapy "White paper" published in 2010; 3 The Beijing Declaration of the International Association of Neurorestoratology; and 4 New legislation passed in Japan in 2014 on regenerative medicine. These recommendations are: greater permissiveness for the use of cell therapy in incurable conditions, identify legitimate cell therapy services, promote medical innovation, respect the rights of patients to choose treatments, recognize the valid compassionate use of unapproved therapies, recognize the significance of small functional gains, give importance to practice-based evidence and existing published literature, have differing regulations for the different types of cell therapies, and adapt the new Japanese legislation for regenerative medicine. Keywords: cellular therapy, stem cells, ethics, regulations, evidence-based medicine, practice-based evidence, Japan regulations, Korea regulations 

  9. Enhanced CAR T cell therapy: A novel approach for head and neck cancers.

    Science.gov (United States)

    Wang, Songlin; Zhu, Zhao

    2018-05-05

    Head and neck cancer that presents in locally advanced stages often results in a bad prognosis with an increased recurrence rate even after curative resections. Radiation therapy is then applied, with multiple side effects, as adjuvant regional therapy. Because of the high rate of recurrence and mortality, new therapies are needed for patients suffering from head and neck malignant tumors.CAR (chimeric antigen receptor) T cell therapy, which was first devised about 25 years ago, causes the killing or apoptosis of target tumor cells through inducing the secretion of cytokines and granzymes by T cells (Cheadle et al., 2014). CARs are comprised of three canonical domains for antigen recognition, T cell activation, and co-stimulation, and are synthetic receptors that reprogram immune cells for therapeutic treatment of multiple tumors (Sadelain, 2017). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  10. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    International Nuclear Information System (INIS)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

    2013-01-01

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24 − /CD44 + ) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer

  11. Advanced cell therapies: targeting, tracking and actuation of cells with magnetic particles.

    Science.gov (United States)

    Connell, John J; Patrick, P Stephen; Yu, Yichao; Lythgoe, Mark F; Kalber, Tammy L

    2015-01-01

    Regenerative medicine would greatly benefit from a new platform technology that enabled measurable, controllable and targeting of stem cells to a site of disease or injury in the body. Superparamagnetic iron-oxide nanoparticles offer attractive possibilities in biomedicine and can be incorporated into cells, affording a safe and reliable means of tagging. This review describes three current and emerging methods to enhance regenerative medicine using magnetic particles to guide therapeutic cells to a target organ; track the cells using MRI and assess their spatial localization with high precision and influence the behavior of the cell using magnetic actuation. This approach is complementary to the systemic injection of cell therapies, thus expanding the horizon of stem cell therapeutics.

  12. Arrhythmogenic consequences of stem cell therapy for cardiac regeneration

    NARCIS (Netherlands)

    Smit, N.W.

    2018-01-01

    A third of the patients that survive a myocardial infarction develop heart failure for which no effective treatment exists. Stem cell therapy could be a possible solution by regeneration of the myocardium. However, the possible electrophysiological effects of interactions between stem cells and

  13. An update clinical application of amniotic fluid-derived stem cells (AFSCs) in cancer cell therapy and tissue engineering.

    Science.gov (United States)

    Gholizadeh-Ghaleh Aziz, Shiva; Fathi, Ezzatollah; Rahmati-Yamchi, Mohammad; Akbarzadeh, Abolfazl; Fardyazar, Zahra; Pashaiasl, Maryam

    2017-06-01

    Recent studies have elucidated that cell-based therapies are promising for cancer treatments. The human amniotic fluid stem (AFS) cells are advantageous cells for such therapeutic schemes that can be innately changed to express therapeutic proteins. HAFSCs display a natural tropism to cancer cells in vivo. They can be useful in cancer cells targeting. Moreover, they are easily available from surplus diagnostic samples during pregnancy and less ethical and legal concern are associated with the collection and application than other putative cells are subjected. This review will designate representatives of amniotic fluid and stem cell derived from amniotic fluid. For this propose, we collect state of human AFS cells data applicable in cancer therapy by dividing this approach into two main classes (nonengineered and engineered based approaches). Our study shows the advantage of AFS cells over other putative cells types in terms differentiation ability to a wide range of cells by potential and effective use in preclinical studies for a variety of diseases. This study has shown the elasticity of human AFS cells and their favorable potential as a multipotent cell source for regenerative stem cell therapy and capable of giving rise to multiple lineages including such as osteoblasts and adipocyte.

  14. Towards safe and effective CD38-CAR T cell therapy for myeloma

    NARCIS (Netherlands)

    Drent, Esther

    2018-01-01

    Immunotherapy is a promising field within cancer therapy. The recent progresses resulted in 'Immunotherapy for the treatment of cancer' as break-through of the year in 2013. This was partly due to the great successes with Chimeric Antigen Receptor (CAR) T cell therapy. With CAR T cells, recognition

  15. Mesenchymal stem cell in venous leg ulcer: An intoxicating therapy.

    Science.gov (United States)

    Athanerey, Anjali; Patra, Pradeep Kumar; Kumar, Awanish

    2017-08-01

    Venous leg ulcers (VLU) are a prevalent and reoccurring type of complicated wound, turning as a considerable public healthcare issue, with critical social and economic concern. There are both medical and surgical therapies to treat venous leg ulcers; however, a cure does not yet exist. Mesenchymal stem cells (MSC) are capable and proved of accelerating wound healing in vivo and their study with human chronic wounds is currently awaited. MSCs are a promising source of adult progenitor cells for cellular therapy and have been demonstrated to differentiate into various mesenchymal cell lineages. They have a crucial and integral role in native wound healing by regulating immune response and inflammation. Improved understanding of the cellular and molecular mechanisms at work in delayed wound healing compels to the development of cellular therapy in VLU. This review focuses on the current treatment option of VLU and further emphasizing the role of MSCs in accelerating the healing process. With further understanding of the mechanism of action of these cells in wound improvement and, the involvement of cytokines can also be revealed that could be used for the therapeutic purpose for VLU healing. Clinical uses of MSCs have been started already, and induced MSCs are surely a promising tool or compelling therapy for VLU. Copyright © 2017 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

  16. A 3D Sphere Culture System Containing Functional Polymers for Large-Scale Human Pluripotent Stem Cell Production

    Directory of Open Access Journals (Sweden)

    Tomomi G. Otsuji

    2014-05-01

    Full Text Available Utilizing human pluripotent stem cells (hPSCs in cell-based therapy and drug discovery requires large-scale cell production. However, scaling up conventional adherent cultures presents challenges of maintaining a uniform high quality at low cost. In this regard, suspension cultures are a viable alternative, because they are scalable and do not require adhesion surfaces. 3D culture systems such as bioreactors can be exploited for large-scale production. However, the limitations of current suspension culture methods include spontaneous fusion between cell aggregates and suboptimal passaging methods by dissociation and reaggregation. 3D culture systems that dynamically stir carrier beads or cell aggregates should be refined to reduce shearing forces that damage hPSCs. Here, we report a simple 3D sphere culture system that incorporates mechanical passaging and functional polymers. This setup resolves major problems associated with suspension culture methods and dynamic stirring systems and may be optimal for applications involving large-scale hPSC production.

  17. Hydroxyurea therapy for sickle cell anemia.

    Science.gov (United States)

    McGann, Patrick T; Ware, Russell E

    2015-01-01

    Sickle cell anemia (SCA) is a severe, inherited hemoglobin disorder affecting 100,000 persons in the US and millions worldwide. Hydroxyurea, a once daily oral medication, has emerged as the primary disease-modifying therapy for SCA. The accumulated body of evidence over 30 years demonstrates that hydroxyurea is a safe and effective therapy for SCA, but hydroxyurea remains underutilized for a variety of reasons. In this review, we summarize the available evidence regarding the pharmacology, clinical, and laboratory benefits, and safety of hydroxyurea therapy for the treatment of SCA. The purpose of this review is to provide the reader a comprehensive understanding of hydroxyurea and to reinforce the fact that hydroxyurea is a safe and effective medication for the treatment of SCA. In our opinion, hydroxyurea therapy should be considered standard-of-care for SCA, representing an essential component of patient management. Early initiation and broader use of hydroxyurea will alter the natural history of SCA, so affected children can live longer and healthier lives. In addition, hydroxyurea use should be extended to low-resource settings such as sub-Saharan Africa, where the burden of SCA and the need for hydroxyurea is arguably the greatest.

  18. Squamous cell carcinoma following radiation therapy for the infiltrative thymoma

    International Nuclear Information System (INIS)

    Ozawa, Shinji; Kitao, Takeshi

    1992-01-01

    This report represents one case of infiltrative thymoma followed by squamous cell carcinoma of the lungs. A 69-year-old man suffered from infiltrative thymoma which reduced by the radiation therapy. Seven years later its replase and the onset of squamous cell carcinoma were found simultaneously. Infiltrative thymoma metastasized not only to the mediastinum but also to the liver and bronchus. Squamous cell carcinoma developed in the right upper lobe. In spite of chemotherapy against them, the patient died. There are many cases in which infiltrative thymoma is accompanied by squamous cell carcinoma of the lung simultaneously; however, secondary onset of squamous cell carcinoma after the radiation therapy of infiltrative thymoma is rare. Secondary carcinogenesis of this case was considered to be closely related with immunological abnormalities caused by thymoma, effects of radiation, smoking and so on. (author)

  19. Apoptosis and cancer stem cells : Implications for apoptosis targeted therapy

    NARCIS (Netherlands)

    Kruyt, Frank A. E.; Schuringa, Jan Jacob

    2010-01-01

    Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited

  20. Research progress in animal models and stem cell therapy for Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Han F

    2014-12-01

    Full Text Available Fabin Han,1,2 Wei Wang1, Chao Chen1 1Centre for Stem Cells and Regenerative Medicine, 2Department of Neurology, Liaocheng People’s Hospital/The Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People’s Republic of China Abstract: Alzheimer’s disease (AD causes degeneration of brain neurons and leads to memory loss and cognitive impairment. Since current therapeutic strategies cannot cure the disease, stem cell therapy represents a powerful tool for the treatment of AD. We first review the advances in molecular pathogenesis and animal models of AD and then discuss recent clinical studies using small molecules and immunoglobulins to target amyloid-beta plaques for AD therapy. Finally, we discuss stem cell therapy for AD using neural stem cells, olfactory ensheathing cells, embryonic stem cells, and mesenchymal stem cell from bone marrow, umbilical cord, and umbilical cord blood. In particular, patient-specific induced pluripotent stem cells are proposed as a future treatment for AD. Keywords: amyloid-beta plaque, neurofibrillary tangle, neural stem cell, olfactory ensheathing cell, mesenchymal stem cell, induced pluripotent stem cell

  1. Brain tumour stem cells: implications for cancer therapy and regenerative medicine.

    Science.gov (United States)

    Sanchez-Martin, Manuel

    2008-09-01

    The cancer relapse and mortality rate suggest that current therapies do not eradicate all malignant cells. Currently, it is accepted that tumorigenesis and organogenesis are similar in many respects, as for example, homeostasis is governed by a distinct sub-population of stem cells in both situations. There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells (CSC), which are characterized by their self-renewing capacity and differentiation ability. The investigation of solid tumour stem cells has gained momentum particularly in the area of brain tumours. Gliomas are the most common type of primary brain tumours. Nearly two-thirds of gliomas are highly malignant lesions with fast progression and unfortunate prognosis. Despite recent advances, two-year survival for glioblastoma (GBM) with optimal therapy is less than 30%. Even among patients with low-grade gliomas that confer a relatively good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and a tumour-initiating function. In general, this fraction is characterized for forming neurospheres, being endowed with drug resistance properties and often, we can isolate some of them using sorting methods with specific antibodies. The molecular characterization of these stem populations will be critical to developing an effective therapy for these tumours with very dismal prognosis. To achieve this aim, the development of a mouse model which recapitulates the nature of these tumours is essential. This review will focus on glioma stem cell knowledge and discuss future implications in brain cancer therapy and regenerative medicine.

  2. Cryopreservation of GABAergic Neuronal Precursors for Cell-Based Therapy.

    Directory of Open Access Journals (Sweden)

    Daniel Rodríguez-Martínez

    Full Text Available Cryopreservation protocols are essential for stem cells storage in order to apply them in the clinic. Here we describe a new standardized cryopreservation protocol for GABAergic neural precursors derived from the medial glanglionic eminence (MGE, a promising source of GABAergic neuronal progenitors for cell therapy against interneuron-related pathologies. We used 10% Me2SO as cryoprotectant and assessed the effects of cell culture amplification and cellular organization, as in toto explants, neurospheres, or individualized cells, on post-thaw cell viability and retrieval. We confirmed that in toto cryopreservation of MGE explants is an optimal preservation system to keep intact the interneuron precursor properties for cell transplantation, together with a high cell viability (>80% and yield (>70%. Post-thaw proliferation and self-renewal of the cryopreserved precursors were tested in vitro. In addition, their migration capacity, acquisition of mature neuronal morphology, and potency to differentiate into multiple interneuron subtypes were also confirmed in vivo after transplantation. The results show that the cryopreserved precursor features remained intact and were similar to those immediately transplanted after their dissection from the MGE. We hope this protocol will facilitate the generation of biobanks to obtain a permanent and reliable source of GABAergic precursors for clinical application in cell-based therapies against interneuronopathies.

  3. The response of CD1d-restricted invariant NKT cells to microbial pathogens and their products

    Directory of Open Access Journals (Sweden)

    Luc eVan Kaer

    2015-05-01

    Full Text Available Invariant natural killer T (iNKT cells become activated during a wide variety of infections. This includes organisms lacking cognate CD1d-binding glycolipid antigens recognized by the semi-invariant T cell receptor of iNKT cells. Additional studies have shown that iNKT cells also become activated in vivo in response to microbial products such as bacterial lipopolysaccharide, a potent inducer of cytokine production in antigen-presenting cells (APCs. Other studies have shown that iNKT cells are highly responsive to stimulation by cytokines such as interleukin-12. These findings have led to the concept that microbial pathogens can activate iNKT cells either directly via glycolipids, or indirectly by inducing cytokine production in APCs. iNKT cells activated in this manner produce multiple cytokines that can influence the outcome of infection, usually in favor of the host, although potent iNKT cell activation may contribute to an uncontrolled cytokine storm and sepsis. One aspect of the response of iNKT cells to microbial pathogens is that it is short-lived and followed by an extended time period of unresponsiveness to reactivation. This refractory period may represent a means to avoid chronic activation and cytokine production by iNKT cells, thus protecting the host against some of the negative effects of iNKT cell activation, but potentially putting the host at risk for secondary infections. These effects of microbial pathogens and their products on iNKT cells are not only important for understanding the role of these cells in immune responses against infections but also for the development of iNKT cell-based therapies.

  4. Radiation therapy following targeted therapy in oligometastatic renal cell carcinoma.

    Science.gov (United States)

    Gravis, Gwenaelle; Faure, Marjorie; Rybikowski, Stanislas; Dermeche, Slimane; Tyran, Marguerite; Calderon, Benoit; Thomassin, Jeanne; Walz, Jochen; Salem, Naji

    2015-11-01

    Up to 40% of patients with renal cell carcinoma (RCC) with initially localized disease eventually develop metastasis following nephrectomy. The current standard of care for metastatic RCC (mRCC) is targeted therapy. However, complete response remains rare. A state of oligometastatic disease may exist, in which metastases are present in a limited number of locations; such cases may benefit from metastasis-directed local therapy, based on the evidence supporting resection of limited-volume metastases, allowing for improved disease control. We retrospectively analyzed 7 cases of response of RCC metastases, in patients treated with targeted therapies followed by radiation therapy (RT) of residual metastatic lesions in Paoli-Calmettes Institute (Marseille, France). We analyzed disease response rates, response to sequential strategy, relapse at the irradiated locations and disease evolution. The median follow-up was 34.1 months (range, 19.2-54.5 months). No progression at the irradiated sites was observed. A total of 5 patients had stable disease at the irradiated locations at the last follow-up; 3 remained in complete remission at the assessment, and 2 were stable. Excellent local response and clinical benefit may be achieved without added toxicity. In conclusion, sequential therapeutic strategies with RT following systemic treatment using sunitinib appear to be highly effective in patients with progressive mRCC and prompt the conduction of further confirmatory trials.

  5. Prevention and treatment of relapse after stem cell transplantation by cellular therapies.

    Science.gov (United States)

    Falkenburg, Fred; Ruggiero, Eliana; Bonini, Chaira; Porter, David; Miller, Jeff; Malard, Floran; Mohty, Mohamad; Kröger, Nicolaus; Kolb, Hans Jochem

    2018-05-24

    Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized.

  6. Mesenchymal stem cell therapy for laryngotracheal stenosis

    DEFF Research Database (Denmark)

    Jakobsen, Kathrine Kronberg; Grønhøj, Christian; Jensen, David H

    2017-01-01

    studies addressing the effect of MSC therapy on the airway. We assessed effect on inflammation, fibrosis, and MSC as a component in tissue engineering for treating defects in the airway. RESULTS: We identified eleven studies (n = 256 animals) from eight countries evaluating the effect of MSCs......BACKGROUND: Laryngotracheal stenosis (LTS) can be either congenital or acquired. Laryngeal stenosis is most often encountered after prolonged intubation. The mechanism for stenosis following intubation is believed to be hypertrophic scarring. Mesenchymal stem cells (MSCs) therapy has shown...... promising results in regenerative medicine. We aimed to systematically review the literature on MSC therapy for stenosis of the conductive airways. METHODS: PubMed, EMBASE, Google Scholar and the Cochrane Library were systematically searched from January 1980-January 2017 with the purpose of identifying all...

  7. Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies?

    DEFF Research Database (Denmark)

    Lepperdinger, Günter; Brunauer, Regina; Jamnig, Angelika

    2008-01-01

    The prospective clinical use of multipotent mesenchymal stromal stem cells (MSC) holds enormous promise for the treatment of a large number of degenerative and age-related diseases. However, the challenges and risks for cell-based therapies are multifaceted. The risks for patients receiving stem ...

  8. Promoting effects of adipose-derived stem cells on breast cancer cells are reversed by radiation therapy.

    Science.gov (United States)

    Baaße, Annemarie; Juerß, Dajana; Reape, Elaine; Manda, Katrin; Hildebrandt, Guido

    2018-04-01

    Partial breast irradiation of early breast cancer patients after lumpectomy and the use of endogenous adipose tissue (AT) for breast reconstruction are promising applications to reduce the side effects of breast cancer therapy. This study tries to investigate the possible risks associated with these therapeutic approaches. It also examines the influence of adipose derived stem cells (ADSCs) as part of the breast cancer microenvironment, and endogenous AT on breast cancer cells following radiation therapy. ADSCs, isolated from human reduction mammoplasties of healthy female donors, exhibited multilineage capacity and specific surface markers. The promoting effects of ADSCs on the growth and survival fraction of breast cancer cells were reversed by treatment with high (8 Gy) or medium (2 Gy) radiation doses. In addition, a suppressing influence on breast cancer growth could be detected by co-culturing with irradiated ADSCs (8 Gy). Furthermore the clonogenic survival of unirradiated tumor cells was reduced by medium of irradiated ADSCs. In conclusion, radiation therapy changed the interactions of ADSCs and breast cancer cells. On the basis of our work, the importance of further studies to exclude potential risks of ADSCs in regenerative applications and radiotherapy has been emphasized.

  9. Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes

    NARCIS (Netherlands)

    Broekgaarden, Mans; Weijer, Ruud; Krekorian, Massis; van den IJssel, Bas; Kos, Milan; Alles, Lindy K.; van Wijk, Albert C.; Bikadi, Zsolt; Hazai, Eszter; van Gulik, Thomas M.; Heger, Michal

    2016-01-01

    Photodynamic therapy (PDT) is a tumor treatment modality in which a tumorlocalized photosensitizer is excited with light, which results in local production of reactive oxygen species, destruction of tumor vasculature, tumor hypoxia, tumor cell death, and induction of an anti-tumor immune response.

  10. [The cell micro-encapsulation techniques and its advancement in the field of gene therapy].

    Science.gov (United States)

    Li, Xiaoling; Cai, Shaohui

    2006-12-01

    It is no doubt that the gene therapy using recombinant engineering cells provides a novel approach to many refractory diseases. However, the transplant rejection from the host's immune system against heterogeneous cells has been the main handicap of its clinical application. The modern cell micro-encapsulation technique with good immune isolation makes it possible to overcome this problem and has shown potential application foreground in clinical therapies for a lot of diseases such as Parkinson's disease and Hemophiliac disease. This article reviews mainly the relative materials and techniques in processing micro-encapsulation, the host cells used to construct the recombinant genetic engineering cells and application of cell micro-encapsulation technique in the field of gene therapy.

  11. Embryonic Stem Cell Therapy of Heart Failure in Genetic Cardiomyopathy

    OpenAIRE

    Yamada, Satsuki; Nelson, Timothy J.; Crespo-Diaz, Ruben J.; Perez-Terzic, Carmen; Liu, Xiao-Ke; Miki, Takashi; Seino, Susumu; Behfar, Atta; Terzic, Andre

    2008-01-01

    Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K+ (KATP) channel sub-units. Embryonic stem cell therapy demonstrates benefit in ischemi...

  12. New development in CAR-T cell therapy.

    Science.gov (United States)

    Wang, Zhenguang; Wu, Zhiqiang; Liu, Yang; Han, Weidong

    2017-02-21

    Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.

  13. New development in CAR-T cell therapy

    Directory of Open Access Journals (Sweden)

    Zhenguang Wang

    2017-02-01

    Full Text Available Abstract Chimeric antigen receptor (CAR-engineered T cells (CAR-T cells have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.

  14. Pre-Clinical Cell-Based Therapy for Limbal Stem Cell Deficiency.

    Science.gov (United States)

    Sehic, Amer; Utheim, Øygunn Aass; Ommundsen, Kristoffer; Utheim, Tor Paaske

    2015-08-28

    The cornea is essential for normal vision by maintaining transparency for light transmission. Limbal stem cells, which reside in the corneal periphery, contribute to the homeostasis of the corneal epithelium. Any damage or disease affecting the function of these cells may result in limbal stem cell deficiency (LSCD). The condition may result in both severe pain and blindness. Transplantation of ex vivo cultured cells onto the cornea is most often an effective therapeutic strategy for LSCD. The use of ex vivo cultured limbal epithelial cells (LEC), oral mucosal epithelial cells, and conjunctival epithelial cells to treat LSCD has been explored in humans. The present review focuses on the current state of knowledge of the many other cell-based therapies of LSCD that have so far exclusively been explored in animal models as there is currently no consensus on the best cell type for treating LSCD. Major findings of all these studies with special emphasis on substrates for culture and transplantation are systematically presented and discussed. Among the many potential cell types that still have not been used clinically, we conclude that two easily accessible autologous sources, epidermal stem cells and hair follicle-derived stem cells, are particularly strong candidates for future clinical trials.

  15. D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

    Science.gov (United States)

    El Sayed, S M; Abou El-Magd, R M; Shishido, Y; Chung, S P; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

    2012-01-01

    Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

  16. B cell repertoires in HLA-sensitized kidney transplant candidates undergoing desensitization therapy.

    Science.gov (United States)

    Beausang, John F; Fan, H Christina; Sit, Rene; Hutchins, Maria U; Jirage, Kshama; Curtis, Rachael; Hutchins, Edward; Quake, Stephen R; Yabu, Julie M

    2017-01-13

    Kidney transplantation is the most effective treatment for end-stage renal disease. Sensitization refers to pre-existing antibodies against human leukocyte antigen (HLA) protein and remains a major barrier to successful transplantation. Despite implementation of desensitization strategies, many candidates fail to respond. Our objective was to determine whether measuring B cell repertoires could differentiate candidates that respond to desensitization therapy. We developed an assay based on high-throughput DNA sequencing of the variable domain of the heavy chain of immunoglobulin genes to measure changes in B cell repertoires in 19 highly HLA-sensitized kidney transplant candidates undergoing desensitization and 7 controls with low to moderate HLA sensitization levels. Responders to desensitization had a decrease of 5% points or greater in cumulated calculated panel reactive antibody (cPRA) levels, and non-responders had no decrease in cPRA. Dominant B cell clones were not observed in highly sensitized candidates, suggesting that the B cells responsible for sensitization are either not present in peripheral blood or present at comparable levels to other circulating B cells. Candidates that responded to desensitization therapy had pre-treatment repertoires composed of a larger fraction of class-switched (IgG and IgA) isotypes compared to non-responding candidates. After B cell depleting therapy, the proportion of switched isotypes increased and the mutation frequencies of the remaining non-switched isotypes (IgM and IgD) increased in both responders and non-responders, perhaps representing a shift in the repertoire towards memory B cells or plasmablasts. Conversely, after transplantation, non-switched isotypes with fewer mutations increased, suggesting a shift in the repertoire towards naïve B cells. Relative abundance of different B cell isotypes is strongly perturbed by desensitization therapy and transplantation, potentially reflecting changes in the relative

  17. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway.

    Science.gov (United States)

    Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D; Gill, Shubhroz; Eichhoff, Ossia M; Seashore-Ludlow, Brinton; Kaffenberger, Samuel D; Eaton, John K; Shimada, Kenichi; Aguirre, Andrew J; Viswanathan, Srinivas R; Chattopadhyay, Shrikanta; Tamayo, Pablo; Yang, Wan Seok; Rees, Matthew G; Chen, Sixun; Boskovic, Zarko V; Javaid, Sarah; Huang, Cherrie; Wu, Xiaoyun; Tseng, Yuen-Yi; Roider, Elisabeth M; Gao, Dong; Cleary, James M; Wolpin, Brian M; Mesirov, Jill P; Haber, Daniel A; Engelman, Jeffrey A; Boehm, Jesse S; Kotz, Joanne D; Hon, Cindy S; Chen, Yu; Hahn, William C; Levesque, Mitchell P; Doench, John G; Berens, Michael E; Shamji, Alykhan F; Clemons, Paul A; Stockwell, Brent R; Schreiber, Stuart L

    2017-07-27

    Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial-mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

  18. Progressing a human embryonic stem-cell-based regenerative medicine therapy towards the clinic.

    Science.gov (United States)

    Whiting, Paul; Kerby, Julie; Coffey, Peter; da Cruz, Lyndon; McKernan, Ruth

    2015-10-19

    Since the first publication of the derivation of human embryonic stem cells in 1998, there has been hope and expectation that this technology will lead to a wave of regenerative medicine therapies with the potential to revolutionize our approach to managing certain diseases. Despite significant resources in this direction, the path to the clinic for an embryonic stem-cell-based regenerative medicine therapy has not proven straightforward, though in the past few years progress has been made. Here, with a focus upon retinal disease, we discuss the current status of the development of such therapies. We also highlight some of our own experiences of progressing a retinal pigment epithelium cell replacement therapy towards the clinic. © 2015 The Author(s).

  19. Trimodal therapy in squamous cell carcinoma of the esophagus

    Directory of Open Access Journals (Sweden)

    Matuschek C

    2011-10-01

    Full Text Available Abstract Patients with ESCC (squamous cell carcinoma of the esophagus are most commonly diagnosed with locally advanced tumor stages. Early metastatic disease and late diagnosis are common reasons responsible for this tumor's poor clinical outcome. The prognosis of esophageal cancer is very poor because patients usually do not have symptoms in early disease stages. Squamous cell carcinoma of the esophagus frequently complicates patients with multiple co-morbidities and these patients often require interdisciplinary diagnosis and treatment procedures. At present time, neoadjuvant radiation therapy and chemotherapy followed by surgery are regarded as the international standard of care. Meta-analyses have confirmed that this approach provides the patient with better local tumor control and an increased overall survival rate. It is recommended that patients with positive tumor response to neoadjuvant therapy and who are poor surgical candidates should consider definitive radiochemotherapy without surgery as a treatment option. In future, EGFR antibodies may also be administered to patients during therapy to improve the current treatment effectiveness. Positron-emission tomography proves to be an early response-imaging tool used to evaluate the effect of the neoadjuvant therapy and could be used as a predictive factor for the survival rate in ESCC. The percentage proportions of residual tumor cells in the histopathological analyses represent a gold standard for evaluating the response rate to radiochemotherapy. In the future, early response evaluation and molecular biological tests could be important diagnostic tools in influencing the treatment decisions of ESCC patients.

  20. Chimeric antigen receptor T cell therapy in pancreatic cancer: from research to practice.

    Science.gov (United States)

    Jindal, Vishal; Arora, Ena; Masab, Muhammad; Gupta, Sorab

    2018-05-04

    Chimeric antigen receptor (CAR) T cell therapy is genetically engineered tumor antigen-specific anticancer immunotherapy, which after showing great success in hematological malignancies is currently being tried in advanced solid tumors like pancreatic cancer. Immunosuppressive tumor microenvironment and dense fibrous stroma are some of the limitation in the success of this novel therapy. However, genetic modifications and combination therapy is the topic of the research to improve its efficacy. In this article, we summarize the current state of knowledge, limitations, and future prospects for CAR T cell therapy in pancreatic cancer.

  1. Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

    International Nuclear Information System (INIS)

    Bernal-Estévez, David; Sánchez, Ramiro; Tejada, Rafael E.; Parra-López, Carlos

    2016-01-01

    Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells. T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy. We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy. Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in

  2. Suitability of small diagnostic peripheral-blood samples for cell-therapy studies.

    Science.gov (United States)

    Stephanou, Coralea; Papasavva, Panayiota; Zachariou, Myria; Patsali, Petros; Epitropou, Marilena; Ladas, Petros; Al-Abdulla, Ruba; Christou, Soteroulla; Antoniou, Michael N; Lederer, Carsten W; Kleanthous, Marina

    2017-02-01

    Primary hematopoietic stem and progenitor cells (HSPCs) are key components of cell-based therapies for blood disorders and are thus the authentic substrate for related research. We propose that ubiquitous small-volume diagnostic samples represent a readily available and as yet untapped resource of primary patient-derived cells for cell- and gene-therapy studies. In the present study we compare isolation and storage methods for HSPCs from normal and thalassemic small-volume blood samples, considering genotype, density-gradient versus lysis-based cell isolation and cryostorage media with different serum contents. Downstream analyses include viability, recovery, differentiation in semi-solid media and performance in liquid cultures and viral transductions. We demonstrate that HSPCs isolated either by ammonium-chloride potassium (ACK)-based lysis or by gradient isolation are suitable for functional analyses in clonogenic assays, high-level HSPC expansion and efficient lentiviral transduction. For cryostorage of cells, gradient isolation is superior to ACK lysis, and cryostorage in freezing media containing 50% fetal bovine serum demonstrated good results across all tested criteria. For assays on freshly isolated cells, ACK lysis performed similar to, and for thalassemic samples better than, gradient isolation, at a fraction of the cost and hands-on time. All isolation and storage methods show considerable variation within sample groups, but this is particularly acute for density gradient isolation of thalassemic samples. This study demonstrates the suitability of small-volume blood samples for storage and preclinical studies, opening up the research field of HSPC and gene therapy to any blood diagnostic laboratory with corresponding bioethics approval for experimental use of surplus material. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Regulatory dendritic cell therapy: from rodents to clinical application.

    Science.gov (United States)

    Raïch-Regué, Dalia; Glancy, Megan; Thomson, Angus W

    2014-10-01

    Dendritic cells (DC) are highly-specialized, bone marrow-derived antigen-presenting cells that induce or regulate innate and adaptive immunity. Regulatory or "tolerogenic" DC play a crucial role in maintaining self tolerance in the healthy steady-state. These regulatory innate immune cells subvert naïve or memory T cell responses by various mechanisms. Regulatory DC (DCreg) also exhibit the ability to induce or restore T cell tolerance in many animal models of autoimmune disease or transplant rejection. There is also evidence that adoptive transfer of DCreg can regulate T cell responses in non-human primates and humans. Important insights gained from in vitro studies and animal models have led recently to the development of clinical grade human DCreg, with potential to treat autoimmune disease or enhance transplant survival while reducing patient dependency on immunosuppressive drugs. Phase I trials have been conducted in type-1 diabetes and rheumatoid arthritis, with results that emphasize the feasibility and safety of DCreg therapy. This mini-review will outline how observations made using animal models have been translated into human use, and discuss the challenges faced in further developing this form of regulatory immune cell therapy in the fields of autoimmunity and transplantation. Copyright © 2013 Elsevier B.V. All rights reserved.

  4. Modelling cell population growth with applications to cancer therapy in human tumour cell lines.

    Science.gov (United States)

    Basse, Britta; Baguley, Bruce C; Marshall, Elaine S; Wake, Graeme C; Wall, David J N

    2004-01-01

    In this paper we present an overview of the work undertaken to model a population of cells and the effects of cancer therapy. We began with a theoretical one compartment size structured cell population model and investigated its asymptotic steady size distributions (SSDs) (On a cell growth model for plankton, MMB JIMA 21 (2004) 49). However these size distributions are not similar to the DNA (size) distributions obtained experimentally via the flow cytometric analysis of human tumour cell lines (data obtained from the Auckland Cancer Society Research Centre, New Zealand). In our one compartment model, size was a generic term, but in order to obtain realistic steady size distributions we chose size to be DNA content and devised a multi-compartment mathematical model for the cell division cycle where each compartment corresponds to a distinct phase of the cell cycle (J. Math. Biol. 47 (2003) 295). We then incorporated another compartment describing the possible induction of apoptosis (cell death) from mitosis phase (Modelling cell death in human tumour cell lines exposed to anticancer drug paclitaxel, J. Math. Biol. 2004, in press). This enabled us to compare our model to flow cytometric data of a melanoma cell line where the anticancer drug, paclitaxel, had been added. The model gives a dynamic picture of the effects of paclitaxel on the cell cycle. We hope to use the model to describe the effects of other cancer therapies on a number of different cell lines. Copyright 2004 Elsevier Ltd.

  5. Cell therapy in dilated cardiomyopathy: from animal models to clinical trials

    Directory of Open Access Journals (Sweden)

    C. del Corsso

    2011-05-01

    Full Text Available Dilated cardiomyopathy can be the end-stage form and common denominator of several cardiac disorders of known cause, such as hypertensive, ischemic, diabetic and Chagasic diseases. However, some individuals have clinical findings, such as an increase in ventricular chamber size and impaired contractility (classical manifestations of dilated cardiomyopathy even in the absence of a diagnosed primary disease. In these patients, dilated cardiomyopathy is classified as idiopathic since its etiology is obscure. Nevertheless, regardless of all of the advances in medical, pharmacological and surgical procedures, the fate of patients with dilated cardiomyopathy (of idiopathic or of any other known cause is linked to arrhythmic episodes, severe congestive heart failure and an increased risk of sudden cardiac death. In this review, we will summarize present data on the use of cell therapies in animal models of dilated cardiomyopathies and will discuss the few clinical trials that have been published so far involving patients affected by this disease. The animal models discussed here include those in which the cardiomyopathy is produced by genetic manipulation and those in which disease is induced by chemical or infectious agents. The specific model used clearly creates restrictions to translation of the proposed cell therapy to clinical practice, insofar as most of the clinical trials performed to date with cell therapy have used autologous cells. Thus, translation of genetic models of dilated cardiomyopathy may have to wait until the use of allogeneic cells becomes more widespread in clinical trials of cell therapies for cardiac diseases.

  6. Premature aging/senescence in cancer cells facing therapy: good or bad?

    Science.gov (United States)

    Gonzalez, Llilians Calvo; Ghadaouia, Sabrina; Martinez, Aurélie; Rodier, Francis

    2016-02-01

    Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions

  7. Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia

    Science.gov (United States)

    Flanagan, Jonathan M.; Howard, Thad A.; Mortier, Nicole; Avlasevich, Svetlana L.; Smeltzer, Matthew P.; Wu, Song; Dertinger, Stephen D.; Ware, Russell E.

    2018-01-01

    Hydroxyurea induces fetal hemoglobin, improves laboratory parameters, and ameliorates clinical complications of sickle cell anemia (SCA), but its long-term efficacy and safety in this patient population remain incompletely defined. Although generally considered non-DNA reactive, an important safety concern is that hydroxyurea may indirectly cause genotoxic damage. To better address this safety issue of hydroxyurea in patients with SCA, we measured the production of micronuclei (MN) in red blood cells (RBC) as a marker of genotoxicity. Blood samples were collected from children with SCA enrolled in the Hydroxyurea Study of Long-term Effects (ClinicalTrials.gov NCT00305175). Flow cytometry quantified circulating MN-containing erythrocyte sub-populations before and during hydroxyurea exposure. The frequency of micronucleated reticulocytes (MN-CD71+) and micronucleated mature erythrocytes (MN-RBC) were then tested for associations with laboratory and clinical data. In cross-sectional analysis of 293 blood samples from 105 children with SCA and a median of 2 years of hydroxyurea therapy, exposure to hydroxyurea was associated with significantly increased frequencies of MN-CD71+ and MN-RBC compared to baseline. The increases were evident by 3 months of therapy, and did not escalate further with up to 12 years of continuous drug exposure. In prospective longitudinal analysis, substantial inter-individual variation in the effect of hydroxyurea on %MN-CD71+ was observed that was associated with the expected laboratory effects of hydroxyurea. In conclusion, clinically relevant exposure to hydroxyurea is associated with increased MN production consistent with erythroblast genotoxicity but with substantial inter-patient variability. Associations between increased %MN-CD71+ and laboratory benefits suggest that hydroxyurea effects on MN production may be related to individual patient sensitivity to hydroxyurea within the bone marrow. PMID:20230905

  8. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    OpenAIRE

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.; Bruns, Christiane J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associa...

  9. Cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema.

    Science.gov (United States)

    Longhini-Dos-Santos, Nathalia; Barbosa-de-Oliveira, Valter Abraão; Kozma, Rodrigo Heras; Faria, Carolina Arruda de; Stessuk, Talita; Frei, Fernando; Ribeiro-Paes, João Tadeu

    2013-04-01

    Emphysema is characterized by destruction of alveolar walls with loss of gas exchange surface and consequent progressive dyspnea. This study aimed to evaluate the efficiency of cell therapy with bone marrow mononuclear cells (BMMC) in an animal model of elastase-induced pulmonary emphysema. Emphysema was induced in C57Bl/J6 female mice by intranasal instillation of elastase. After 21 days, the mice received bone marrow mononuclear cells from EGFP male mice with C57Bl/J6 background. The groups were assessed by comparison and statistically significant differences (p pulmonary emphysema.

  10. Towards the standardization of stem cell therapy studies for ischemic heart diseases: Bridging the gap between animal models and the clinical setting.

    Science.gov (United States)

    Trindade, Fábio; Leite-Moreira, Adelino; Ferreira-Martins, João; Ferreira, Rita; Falcão-Pires, Inês; Vitorino, Rui

    2017-02-01

    Today there is an increasing demand for heart transplantations for patients diagnosed with heart failure. Though, shortage of donors as well as the large number of ineligible patients hurdle such treatment option. This, in addition to the considerable number of transplant rejections, has driven the clinical research towards the field of regenerative medicine. Nonetheless, to date, several stem cell therapies tested in animal models fall by the wayside and when they meet the criteria to clinical trials, subjects often exhibit modest improvements. A main issue slowing down the admission of such therapies in the domain of human trials is the lack of protocol standardization between research groups, which hampers comparison between different approaches as well as the lack of thought regarding the clinical translation. In this sense, given the large amount of reports on stem cell therapy studies in animal models reported in the last 3years, we sought to evaluate their advantages and limitations towards the clinical setting and provide some suggestions for the forthcoming investigations. We expect, with this review, to start a new paradigm on regenerative medicine, by evoking the debate on how to plan novel stem cell therapy studies with animal models in order to achieve more consistent scientific production and accelerate the admission of stem cell therapies in the clinical setting. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma

    Science.gov (United States)

    Ren, Pei-pei; Li, Ming; Li, Tian-fang; Han, Shuang-yin

    2017-01-01

    Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. PMID:28302023

  12. Metastasis in renal cell carcinoma: Biology and implications for therapy

    Directory of Open Access Journals (Sweden)

    Jun Gong

    2016-10-01

    Full Text Available Although multiple advances have been made in systemic therapy for renal cell carcinoma (RCC, metastatic RCC remains incurable. In the current review, we focus on the underlying biology of RCC and plausible mechanisms of metastasis. We further outline evolving strategies to combat metastasis through adjuvant therapy. Finally, we discuss clinical patterns of metastasis in RCC and how distinct systemic therapy approaches may be considered based on the anatomic location of metastasis.

  13. Exploiting natural killer group 2D receptors for CAR T-cell therapy.

    Science.gov (United States)

    Demoulin, Benjamin; Cook, W James; Murad, Joana; Graber, David J; Sentman, Marie-Louise; Lonez, Caroline; Gilham, David E; Sentman, Charles L; Agaugue, Sophie

    2017-08-01

    Chimeric antigen receptors (CARs) are genetically engineered proteins that combine an extracellular antigen-specific recognition domain with one or several intracellular T-cell signaling domains. When expressed in T cells, these CARs specifically trigger T-cell activation upon antigen recognition. While the clinical proof of principle of CAR T-cell therapy has been established in hematological cancers, CAR T cells are only at the early stages of being explored to tackle solid cancers. This special report discusses the concept of exploiting natural killer cell receptors as an approach that could broaden the specificity of CAR T cells and potentially enhance the efficacy of this therapy against solid tumors. New data demonstrating feasibility of this approach in humans and supporting the ongoing clinical trial are also presented.

  14. Stem Cell-Based Therapies for Polyglutamine Diseases.

    Science.gov (United States)

    Mendonça, Liliana S; Onofre, Isabel; Miranda, Catarina Oliveira; Perfeito, Rita; Nóbrega, Clévio; de Almeida, Luís Pereira

    2018-01-01

    Polyglutamine (polyQ) diseases are a family of neurodegenerative disorders with very heterogeneous clinical presentations, although with common features such as progressive neuronal death. Thus, at the time of diagnosis patients might present an extensive and irreversible neuronal death demanding cell replacement or support provided by cell-based therapies. For this purpose stem cells, which include diverse populations ranging from embryonic stem cells (ESCs), to fetal stem cells, mesenchymal stromal cells (MSCs) or induced pluripotent stem cells (iPSCs) have remarkable potential to promote extensive brain regeneration and recovery in neurodegenerative disorders. This regenerative potential has been demonstrated in exciting pre and clinical assays. However, despite these promising results, several drawbacks are hampering their successful clinical implementation. Problems related to ethical issues, quality control of the cells used and the lack of reliable models for the efficacy assessment of human stem cells. In this chapter the main advantages and disadvantages of the available sources of stem cells as well as their efficacy and potential to improve disease outcomes are discussed.

  15. Metabolic flux profiling of MDCK cells during growth and canine adenovirus vector production.

    Science.gov (United States)

    Carinhas, Nuno; Pais, Daniel A M; Koshkin, Alexey; Fernandes, Paulo; Coroadinha, Ana S; Carrondo, Manuel J T; Alves, Paula M; Teixeira, Ana P

    2016-03-23

    Canine adenovirus vector type 2 (CAV2) represents an alternative to human adenovirus vectors for certain gene therapy applications, particularly neurodegenerative diseases. However, more efficient production processes, assisted by a greater understanding of the effect of infection on producer cells, are required. Combining [1,2-(13)C]glucose and [U-(13)C]glutamine, we apply for the first time (13)C-Metabolic flux analysis ((13)C-MFA) to study E1-transformed Madin-Darby Canine Kidney (MDCK) cells metabolism during growth and CAV2 production. MDCK cells displayed a marked glycolytic and ammoniagenic metabolism, and (13)C data revealed a large fraction of glutamine-derived labelling in TCA cycle intermediates, emphasizing the role of glutamine anaplerosis. (13)C-MFA demonstrated the importance of pyruvate cycling in balancing glycolytic and TCA cycle activities, as well as occurrence of reductive alphaketoglutarate (AKG) carboxylation. By turn, CAV2 infection significantly upregulated fluxes through most central metabolism, including glycolysis, pentose-phosphate pathway, glutamine anaplerosis and, more prominently, reductive AKG carboxylation and cytosolic acetyl-coenzyme A formation, suggestive of increased lipogenesis. Based on these results, we suggest culture supplementation strategies to stimulate nucleic acid and lipid biosynthesis for improved canine adenoviral vector production.

  16. Stem Cells Derived from Amniotic Fluid: A Potential Pluripotent-Like Cell Source for Cellular Therapy?

    Science.gov (United States)

    Ramasamy, Thamil Selvee; Velaithan, Vithya; Yeow, Yelena; Sarkar, Fazlul H

    2018-01-01

    Regenerative medicine aims to provide therapeutic treatment for disease or injury, and cell-based therapy is a newer therapeutic approach different from conventional medicine. Ethical issues that rose by the utilisation of human embryonic stem cells (hESC) and the limited capacity of adult stem cells, however, hinder the application of these stem cells in regenerative medicine. Recently, isolation and characterisation of c-kit positive cells from human amniotic fluid, which possess intermediate characteristics between hESCs and adult stem cells, provided a new approach towards realising their promise for fetal and adult regenerative medicine. Despite the number of studies that have been initiated to characterize their molecular signature, research on developing approaches to maintain and enhance their regenerative potential is urgently needed and must be developed. Thus, this review is focused on understanding their potential uses and factors influencing their pluripotent status in vitro. In short, this cell source could be an ideal cellular resource for pluripotent cells for potential applications in allogeneic cellular replacement therapies, fetal tissue engineering, pharmaceutical screening, and in disease modelling. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Mapping {sup 15}O Production Rate for Proton Therapy Verification

    Energy Technology Data Exchange (ETDEWEB)

    Grogg, Kira; Alpert, Nathaniel M.; Zhu, Xuping [Center for Advanced Radiological Sciences, Nuclear Medicine and Molecular Imaging, Radiology Department, Massachusetts General Hospital, Boston, Massachusetts (United States); Min, Chul Hee [Department of Radiological Science, College of Health Science, Yonsei University, Wonju, Kangwon (Korea, Republic of); Testa, Mauro; Winey, Brian [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); Normandin, Marc D. [Center for Advanced Radiological Sciences, Nuclear Medicine and Molecular Imaging, Radiology Department, Massachusetts General Hospital, Boston, Massachusetts (United States); Shih, Helen A.; Paganetti, Harald; Bortfeld, Thomas [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (United States); El Fakhri, Georges, E-mail: elfakhri@pet.mgh.harvard.edu [Center for Advanced Radiological Sciences, Nuclear Medicine and Molecular Imaging, Radiology Department, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2015-06-01

    Purpose: This work was a proof-of-principle study for the evaluation of oxygen-15 ({sup 15}O) production as an imaging target through the use of positron emission tomography (PET), to improve verification of proton treatment plans and to study the effects of perfusion. Methods and Materials: Dynamic PET measurements of irradiation-produced isotopes were made for a phantom and rabbit thigh muscles. The rabbit muscle was irradiated and imaged under both live and dead conditions. A differential equation was fitted to phantom and in vivo data, yielding estimates of {sup 15}O production and clearance rates, which were compared to live versus dead rates for the rabbit and to Monte Carlo predictions. Results: PET clearance rates agreed with decay constants of the dominant radionuclide species in 3 different phantom materials. In 2 oxygen-rich materials, the ratio of {sup 15}O production rates agreed with the expected ratio. In the dead rabbit thighs, the dynamic PET concentration histories were accurately described using {sup 15}O decay constant, whereas the live thigh activity decayed faster. Most importantly, the {sup 15}O production rates agreed within 2% (P>.5) between conditions. Conclusions: We developed a new method for quantitative measurement of {sup 15}O production and clearance rates in the period immediately following proton therapy. Measurements in the phantom and rabbits were well described in terms of {sup 15}O production and clearance rates, plus a correction for other isotopes. These proof-of-principle results support the feasibility of detailed verification of proton therapy treatment delivery. In addition, {sup 15}O clearance rates may be useful in monitoring permeability changes due to therapy.

  18. Therapy-related AML/MDS after treatment of low-grade B-cell lymphoma

    International Nuclear Information System (INIS)

    Yanada, Masamitsu

    2008-01-01

    Described is the therapy-related AML (acute myelogenetic leukemia)/MDS (myelo-dysplasia syndrome), which is manifested after various treatments of low-grade B-cell lymphoma and has strongly attracted attention because of the markedly improved prognosis due to recent advantages of the therapy for the disease. AML/MDS occurs several years after chemotherapy and/or radiation therapy which cause DNA damage in hematopoietic cells, and the AML/MDS risk is known increased in patients undergone especially with autologous transplantation of those cells. AML/MDS has the feature similar to that caused either by alkylating agent or by topoisomerase-2 inhibitor, and the disease by radiation belong to the former. Yet unclear is the problem whether malignant cells causing the disease after therapy are derived from the remaining cells in the graft or in the body. Although irradiations of total body and total lymphaden as well as chemotherapy are said to be related to AML/MDS and local irradiation does not contribute to its risk, the most important factor for the disease is considered to be the autotransplantation as the recurrence occurs in 50% after it. Thus the treatment history should be taken into consideration for suppressing AML/MDS, for which follow up with consideration for the disease is required particularly after autotransplantation. (R.T.)

  19. Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

    Science.gov (United States)

    Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

    2016-08-01

    Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited.

  20. Production of oncolytic adenovirus and human mesenchymal stem cells in a single-use, Vertical-Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier-based cell culture processes.

    Science.gov (United States)

    Sousa, Marcos F Q; Silva, Marta M; Giroux, Daniel; Hashimura, Yas; Wesselschmidt, Robin; Lee, Brian; Roldão, António; Carrondo, Manuel J T; Alves, Paula M; Serra, Margarida

    2015-01-01

    Anchorage-dependent cell cultures are used for the production of viruses, viral vectors, and vaccines, as well as for various cell therapies and tissue engineering applications. Most of these applications currently rely on planar technologies for the generation of biological products. However, as new cell therapy product candidates move from clinical trials towards potential commercialization, planar platforms have proven to be inadequate to meet large-scale manufacturing demand. Therefore, a new scalable platform for culturing anchorage-dependent cells at high cell volumetric concentrations is urgently needed. One promising solution is to grow cells on microcarriers suspended in single-use bioreactors. Toward this goal, a novel bioreactor system utilizing an innovative Vertical-Wheel™ technology was evaluated for its potential to support scalable cell culture process development. Two anchorage-dependent human cell types were used: human lung carcinoma cells (A549 cell line) and human bone marrow-derived mesenchymal stem cells (hMSC). Key hydrodynamic parameters such as power input, mixing time, Kolmogorov length scale, and shear stress were estimated. The performance of Vertical-Wheel bioreactors (PBS-VW) was then evaluated for A549 cell growth and oncolytic adenovirus type 5 production as well as for hMSC expansion. Regarding the first cell model, higher cell growth and number of infectious viruses per cell were achieved when compared with stirred tank (ST) bioreactors. For the hMSC model, although higher percentages of proliferative cells could be reached in the PBS-VW compared with ST bioreactors, no significant differences in the cell volumetric concentration and expansion factor were observed. Noteworthy, the hMSC population generated in the PBS-VW showed a significantly lower percentage of apoptotic cells as well as reduced levels of HLA-DR positive cells. Overall, these results showed that process transfer from ST bioreactor to PBS-VW, and scale-up was

  1. Anti-B cell antibody therapies for inflammatory rheumatic diseases

    DEFF Research Database (Denmark)

    Faurschou, Mikkel; Jayne, David R W

    2014-01-01

    Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti-B cell antibody-based therapies for rheumatoid arthritis, systemic lupus...... and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti-B cell antibodies....

  2. B-cell-depleting Therapy in Systemic Lupus Erythematosus

    Science.gov (United States)

    Ramos-Casals, Manuel; Sanz, Iñaki; Bosch, Xavier; Stone, John H.; Khamashta, Munther A.

    2014-01-01

    The emergence of a new class of agents (B-cell-depleting therapies) has opened a new era in the therapeutic approach to systemic lupus erythematosus, with belimumab being the first drug licensed for use in systemic lupus erythematosus in more than 50 years. Four agents deserve specific mention: rituximab, ocrelizumab, epratuzumab, and belimumab. Controlled trials have shown negative results for rituximab, promising results for epratuzumab, and positive results for belimumab. Despite these negative results, rituximab is the most-used agent in patients who do not respond or are intolerant to standard therapy and those with life-threatening presentations. B-cell-depleting agents should not be used in patients with mild disease and should be tailored according to individual patient characteristics, including ethnicity, organ involvement, and the immunological profile. Forthcoming studies of B-cell-directed strategies, particularly data from investigations of off-label rituximab use and postmarketing studies of belimumab, will provide new insights into the utility of these treatments in the routine management of patients with systemic lupus erythematosus. PMID:22444096

  3. Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells.

    Science.gov (United States)

    Udalamaththa, Vindya Lankika; Jayasinghe, Chanika Dilumi; Udagama, Preethi Vidya

    2016-08-11

    Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material

  4. Infrapatellar Fat Pad Stem Cells: From Developmental Biology to Cell Therapy

    Directory of Open Access Journals (Sweden)

    Ronaldo J. F. C. do Amaral

    2017-01-01

    Full Text Available The ideal cell type to be used for cartilage therapy should possess a proven chondrogenic capacity, not cause donor-site morbidity, and should be readily expandable in culture without losing their phenotype. There are several cell sources being investigated to promote cartilage regeneration: mature articular chondrocytes, chondrocyte progenitors, and various stem cells. Most recently, stem cells isolated from joint tissue, such as chondrogenic stem/progenitors from cartilage itself, synovial fluid, synovial membrane, and infrapatellar fat pad (IFP have gained great attention due to their increased chondrogenic capacity over the bone marrow and subcutaneous adipose-derived stem cells. In this review, we first describe the IFP anatomy and compare and contrast it with other adipose tissues, with a particular focus on the embryological and developmental aspects of the tissue. We then discuss the recent advances in IFP stem cells for regenerative medicine. We compare their properties with other stem cell types and discuss an ontogeny relationship with other joint cells and their role on in vivo cartilage repair. We conclude with a perspective for future clinical trials using IFP stem cells.

  5. Infrapatellar Fat Pad Stem Cells: From Developmental Biology to Cell Therapy.

    Science.gov (United States)

    do Amaral, Ronaldo J F C; Almeida, Henrique V; Kelly, Daniel J; O'Brien, Fergal J; Kearney, Cathal J

    2017-01-01

    The ideal cell type to be used for cartilage therapy should possess a proven chondrogenic capacity, not cause donor-site morbidity, and should be readily expandable in culture without losing their phenotype. There are several cell sources being investigated to promote cartilage regeneration: mature articular chondrocytes, chondrocyte progenitors, and various stem cells. Most recently, stem cells isolated from joint tissue, such as chondrogenic stem/progenitors from cartilage itself, synovial fluid, synovial membrane, and infrapatellar fat pad (IFP) have gained great attention due to their increased chondrogenic capacity over the bone marrow and subcutaneous adipose-derived stem cells. In this review, we first describe the IFP anatomy and compare and contrast it with other adipose tissues, with a particular focus on the embryological and developmental aspects of the tissue. We then discuss the recent advances in IFP stem cells for regenerative medicine. We compare their properties with other stem cell types and discuss an ontogeny relationship with other joint cells and their role on in vivo cartilage repair. We conclude with a perspective for future clinical trials using IFP stem cells.

  6. Impact of nanotechnology on the delivery of natural products for cancer prevention and therapy.

    Science.gov (United States)

    Siddiqui, Imtiaz A; Sanna, Vanna

    2016-06-01

    Chemoprevention of human cancer by dietary products is a practical approach of cancer control, especially when chemoprevention is involved during the early stages of the carcinogenesis process. Research over the last few decades has clearly demonstrated the efficacy of dietary products for chemoprevention in cell culture and preclinical animal model systems. However, these in vitro and in vivo effects have not been able to be translated to bedside for clinical use. Among many reasons, inefficient systemic delivery and bioavailability of promising chemopreventive agents are considered to significantly contribute to such a disconnection. Since its advent in the field of cancer, nanotechnology has provided researchers with expertise to explore new avenues for diagnosis, prevention, and therapy of the disease. In a similar trait, we introduced a novel concept in which nanotechnology was utilized for enhancing the outcome of chemoprevention (Cancer Res. 2009; 69:1712-1716). This idea, which we termed as 'nanochemoprevention', was exploited by several laboratories and has now become an advancing field in chemoprevention research. This review summarizes some of these applications of nanotechnology in medicine, particularly focused on controlled and sustained release of bioactive compounds with emphasis on current and future utilization of nanochemoprevention for prevention and therapy of cancer. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. An official American Thoracic Society workshop report: stem cells and cell therapies in lung biology and diseases.

    Science.gov (United States)

    Weiss, Daniel J; Chambers, Daniel; Giangreco, Adam; Keating, Armand; Kotton, Darrell; Lelkes, Peter I; Wagner, Darcy E; Prockop, Darwin J

    2015-04-01

    The University of Vermont College of Medicine and the Vermont Lung Center, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, European Respiratory Society, International Society for Cell Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 29 to August 1, 2013 at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell-based therapies for lung diseases. This conference was a follow-up to four previous biennial conferences held at the University of Vermont in 2005, 2007, 2009, and 2011. Each of those conferences, also sponsored by the National Institutes of Health, American Thoracic Society, and Respiratory Disease Foundations, has been important in helping guide research and funding priorities. The major conference recommendations are summarized at the end of the report and highlight both the significant progress and major challenges in these rapidly progressing fields.

  8. The Application of Nanomaterials in Stem Cell Therapy for Some Neurological Diseases.

    Science.gov (United States)

    Zhang, Guilong; Khan, Ahsan Ali; Wu, Hao; Chen, Lukui; Gu, Yuchun; Gu, Ning

    2018-02-08

    Stem cell therapy provides great promising therapeutic benefits for various neurological disorders. Cell transplantation has emerged as cell replacement application for nerve damage. Recently, nanomaterials obtain wide development in various industrial and medical fields, and nanoparticles have been applied in the neurological field for tracking and treating nervous system diseases. Combining stem cells with nanotechnology has raised more and more attentions; and it has demonstrated that the combination has huge effects on clinical diagnosis and therapeutics in multiple central nervous system diseases, meanwhile, improves prognosis. The aim of this review was to give a brief overview of the application of nanomaterials in stem cell therapy for neurological diseases. Nanoparticles not only promote stem cell proliferation and differentiation in vitro or in vivo, but also play dominant roles on stem cell imaging and tracking. Furthermore, via delivering genes or drugs, nanoparticles can participate in stem cell therapeutic applications for various neurological diseases, such as ischemic stroke, spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and gliomas. However, nanoparticles have potential cytotoxic effects on nerve cells, which are related to their physicochemical properties. Nano-stem cell-based therapy as a promising strategy has the ability to affect neuronal repair and regeneration in the central nervous system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Generating a Tolerogenic Cell Therapy Knowledge Graph from Literature

    Directory of Open Access Journals (Sweden)

    Andre Lamurias

    2017-11-01

    Full Text Available Tolerogenic cell therapies provide an alternative to conventional immunosuppressive treatments of autoimmune disease and address, among other goals, the rejection of organ or stem cell transplants. Since various methodologies can be followed to develop tolerogenic therapies, it is important to be aware and up to date on all available studies that may be relevant to their improvement. Recently, knowledge graphs have been proposed to link various sources of information, using text mining techniques. Knowledge graphs facilitate the automatic retrieval of information about the topics represented in the graph. The objective of this work was to automatically generate a knowledge graph for tolerogenic cell therapy from biomedical literature. We developed a system, ICRel, based on machine learning to extract relations between cells and cytokines from abstracts. Our system retrieves related documents from PubMed, annotates each abstract with cell and cytokine named entities, generates the possible combinations of cell–cytokine pairs cooccurring in the same sentence, and identifies meaningful relations between cells and cytokines. The extracted relations were used to generate a knowledge graph, where each edge was supported by one or more documents. We obtained a graph containing 647 cell–cytokine relations, based on 3,264 abstracts. The modules of ICRel were evaluated with cross-validation and manual evaluation of the relations extracted. The relation extraction module obtained an F-measure of 0.789 in a reference database, while the manual evaluation obtained an accuracy of 0.615. Even though the knowledge graph is based on information that was already published in other articles about immunology, the system we present is more efficient than the laborious task of manually reading all the literature to find indirect or implicit relations. The ICRel graph will help experts identify implicit relations that may not be evident in published studies.

  10. Mesenchymal stromal cell therapy in ischemic heart disease

    DEFF Research Database (Denmark)

    Kastrup, Jens; Mygind, Naja Dam; Ali Qayyum, Abbas

    2016-01-01

    is very costly for the health care system. Therefore, new treatment options and strategies are being researched intensely. Stem cell therapy to improve myocardial perfusion and stimulate growth of new cardiomyocytes could be a new way to go. Nevertheless, the results from clinical studies have varied...... considerably, probably due to the use of many different cell lines obtained from different tissues and the different patient populations. The present review will focus on treatment with the mesenchymal stromal cell from bone marrow and adipose tissue in animal and patients with acute and chronic IHD (CIHD)....

  11. Improvement of adipose tissue-derived cells by low-energy extracorporeal shock wave therapy.

    Science.gov (United States)

    Priglinger, Eleni; Schuh, Christina M A P; Steffenhagen, Carolin; Wurzer, Christoph; Maier, Julia; Nuernberger, Sylvia; Holnthoner, Wolfgang; Fuchs, Christiane; Suessner, Susanne; Rünzler, Dominik; Redl, Heinz; Wolbank, Susanne

    2017-09-01

    Cell-based therapies with autologous adipose tissue-derived cells have shown great potential in several clinical studies in the last decades. The majority of these studies have been using the stromal vascular fraction (SVF), a heterogeneous mixture of fibroblasts, lymphocytes, monocytes/macrophages, endothelial cells, endothelial progenitor cells, pericytes and adipose-derived stromal/stem cells (ASC) among others. Although possible clinical applications of autologous adipose tissue-derived cells are manifold, they are limited by insufficient uniformity in cell identity and regenerative potency. In our experimental set-up, low-energy extracorporeal shock wave therapy (ESWT) was performed on freshly obtained human adipose tissue and isolated adipose tissue SVF cells aiming to equalize and enhance stem cell properties and functionality. After ESWT on adipose tissue we could achieve higher cellular adenosine triphosphate (ATP) levels compared with ESWT on the isolated SVF as well as the control. ESWT on adipose tissue resulted in a significantly higher expression of single mesenchymal and vascular marker compared with untreated control. Analysis of SVF protein secretome revealed a significant enhancement in insulin-like growth factor (IGF)-1 and placental growth factor (PLGF) after ESWT on adipose tissue. Summarizing we could show that ESWT on adipose tissue enhanced the cellular ATP content and modified the expression of single mesenchymal and vascular marker, and thus potentially provides a more regenerative cell population. Because the effectiveness of autologous cell therapy is dependent on the therapeutic potency of the patient's cells, this technology might raise the number of patients eligible for autologous cell transplantation. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  12. Intracellular Hyper-Acidification Potentiated by Hydrogen Sulfide Mediates Invasive and Therapy Resistant Cancer Cell Death

    Directory of Open Access Journals (Sweden)

    Zheng-Wei Lee

    2017-10-01

    Full Text Available Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active. We characterized and utilized cancer cell line pairs of various organ origins, based on their aggressive behaviors, and assessed their response to GYY4137. We compared glycolytic activity, via lactate production, and intracellular pH of each cancer cell line pair after exposure to H2S. Invasive and therapy resistant cancers, collectively termed aggressive cancers, are receptive to H2S-mediated cytotoxicity, albeit at a higher concentration of GYY4137 donor. While lactate production was enhanced, intracellular pH of aggressive cancers was only modestly decreased. Inherently, the magnitude of intracellular pH decrease is a key determinant for cancer cell sensitivity to H2S. We demonstrated the utility of coupling GYY4137 with either simvastatin, known to inhibit monocarboxylate transporter 4 (MCT4, or metformin, to further boost glycolysis, in bringing about cell death for aggressive cancers. Simvastatin inhibiting lactate extrusion thence contained excess lactate induced by GYY4137 within intracellular compartment. In contrast, the combined exposure to both GYY4137 and metformin overwhelms cancer cells with lactate over-production exceeding its expulsion rate. Together, GYY4137 and simvastatin or metformin synergize to induce intracellular hyper-acidification-mediated cancer cell death.

  13. Progress of stem/progenitor cell-based therapy for retinal degeneration.

    Science.gov (United States)

    Tang, Zhimin; Zhang, Yi; Wang, Yuyao; Zhang, Dandan; Shen, Bingqiao; Luo, Min; Gu, Ping

    2017-05-10

    Retinal degeneration (RD), such as age-related macular degeneration (AMD) and retinitis pigmentosa, is one of the leading causes of blindness. Presently, no satisfactory therapeutic options are available for these diseases principally because the retina and retinal pigmented epithelium (RPE) do not regenerate, although wet AMD can be prevented from further progression by anti-vascular endothelial growth factor therapy. Nevertheless, stem/progenitor cell approaches exhibit enormous potential for RD treatment using strategies mainly aimed at the rescue and replacement of photoreceptors and RPE. The sources of stem/progenitor cells are classified into two broad categories in this review, which are (1) ocular-derived progenitor cells, such as retinal progenitor cells, and (2) non-ocular-derived stem cells, including embryonic stem cells, induced pluripotent stem cells, and mesenchymal stromal cells. Here, we discuss in detail the progress in the study of four predominant stem/progenitor cell types used in animal models of RD. A short overview of clinical trials involving the stem/progenitor cells is also presented. Currently, stem/progenitor cell therapies for RD still have some drawbacks such as inhibited proliferation and/or differentiation in vitro (with the exception of the RPE) and limited long-term survival and function of grafts in vivo. Despite these challenges, stem/progenitor cells represent the most promising strategy for RD treatment in the near future.

  14. Identification of Hematopoietic Stem Cell Engraftment Genes in Gene Therapy Studies.

    Science.gov (United States)

    Powers, John M; Trobridge, Grant D

    2013-09-01

    Hematopoietic stem cell (HSC) therapy using replication-incompetent retroviral vectors is a promising approach to provide life-long correction for genetic defects. HSC gene therapy clinical studies have resulted in functional cures for several diseases, but in some studies clonal expansion or leukemia has occurred. This is due to the dyregulation of endogenous host gene expression from vector provirus insertional mutagenesis. Insertional mutagenesis screens using replicating retroviruses have been used extensively to identify genes that influence oncogenesis. However, retroviral mutagenesis screens can also be used to determine the role of genes in biological processes such as stem cell engraftment. The aim of this review is to describe the potential for vector insertion site data from gene therapy studies to provide novel insights into mechanisms of HSC engraftment. In HSC gene therapy studies dysregulation of host genes by replication-incompetent vector proviruses may lead to enrichment of repopulating clones with vector integrants near genes that influence engraftment. Thus, data from HSC gene therapy studies can be used to identify novel candidate engraftment genes. As HSC gene therapy use continues to expand, the vector insertion site data collected will be of great interest to help identify novel engraftment genes and may ultimately lead to new therapies to improve engraftment.

  15. Radiation therapy for the treatment of feline advanced cutaneous squamous cell carcinoma

    International Nuclear Information System (INIS)

    Cunha, S.C.S.; Corgozinho, K.B.; Ferreira, A.M.R; Carvalho, L.A.V.; Holguin, P.G.

    2014-01-01

    The efficacy of radiation therapy for feline advanced cutaneous squamous cell carcinoma was evaluated. A full course radiation therapy protocol was applied to six cats showing single or multiple facial squamous cell carcinomas, in a total of seven histologically confirmed neoplastic lesions. Of the lesions, one was staged as T 1 , and six as T 4 according to WHO staging system of epidermal tumors. The animals were submitted to twelve radiation fractions of 4 Gy each, on a Monday-Wednesday-Friday schedule, and the equipment used was an orthovoltage unit. Energy used was 120 kV, 15 mA and 2 mm aluminum filter. The cats were evaluated during the treatment and 30 and 60 days after the end of the radiation therapy. In this study, 87% of the lesions had complete remission and 13% partial remission to the treatment. Side effects were considered mild according to Veterinary Radiation Therapy Oncology Group Toxicity criteria, and included erythema, epilation and rhinitis. Radiation Therapy was considered safe for feline cutaneous squamous cell carcinoma, leading to mild side effects and can represent a good therapeutic option. (author)

  16. Parthenogenetic embryonic stem cells with H19 siRNA-mediated knockdown as a potential resource for cell therapy.

    Science.gov (United States)

    Kwak, Minhye; Hong, Su; Yu, Seong-Lan; Sim, Bo-Woong; Seo, Jeong-Sun; Kang, Jaeku

    2012-02-01

    Embryonic stem (ES) cells are used in cell therapy and tissue engineering due to their ability to produce different cells types. However, studies of ES cells that are derived from fertilized embryos have raised concerns about the limitations imposed by ethical and political considerations. Therefore, many studies of stem cells use the stem cells that are derived from unfertilized oocytes and adult tissue. Although parthenogenetic embryonic stem (ESP) cells also avoid ethical and political dilemmas and can be used in cell-based therapy, the ESP cells exhibit growth retardation problems. Therefore, to investigate the potential for muscle growth from genetically modified ESP cells, we established four ES cell types, including normal embryonic stem (ESN) cells, ESP cells, ESP cells that overexpress the insulin-like growth factor 2 (Igf2) gene (ESI) and ESP cells with down-regulated H19 gene expression (ESH). Using these cells, we examined the expression profiles of genes that were related to imprinting and muscle using microarrays. The gene expression patterns of ESI and ESH cells were similar and were more closely related to the ESN pattern than that of the ESP cells. Differentiated ESH cells exhibited increased expression of bone morphologic protein 4 (BMP4), which is a mesoderm marker, compared with the differentiated ESI cells. We showed that Igf2 expression was induced by H19 silencing in the ESP cells via hypermethylation of the H19 imprinting control region 1 (ICR1). Moreover, the proportion of ESH-derived chimera was slightly higher than those produced from the ESP cells. In addition, we detected increased cell proliferation in the MEF cells following H19 knock-down. These results indicate that the ESH cells may be a source of cell-based therapy for conditions such as muscular atrophy.

  17. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy.

    Science.gov (United States)

    Liu, Lin; Lee, Wang-Sik; Doray, Balraj; Kornfeld, Stuart

    2017-06-16

    Several lysosomal enzymes currently used for enzyme replacement therapy in patients with lysosomal storage diseases contain very low levels of mannose 6-phosphate, limiting their uptake via mannose 6-phosphate receptors on the surface of the deficient cells. These enzymes are produced at high levels by mammalian cells and depend on endogenous GlcNAc-1-phosphotransferase α/β precursor to phosphorylate the mannose residues on their glycan chains. We show that co-expression of an engineered truncated GlcNAc-1-phosphotransferase α/β precursor and the lysosomal enzyme of interest in the producing cells resulted in markedly increased phosphorylation and cellular uptake of the secreted lysosomal enzyme. This method also results in the production of highly phosphorylated acid β-glucocerebrosidase, a lysosomal enzyme that normally has just trace amounts of this modification.

  18. A global comparative overview of the legal regulation of stem cell research and therapy: Lessons for South Africa

    Directory of Open Access Journals (Sweden)

    Melodie Slabbert

    2015-09-01

    Full Text Available Stem cell research and its potential translation to regenerative medicine, tissue engineering and cell and gene therapy, have led to controversy and debates similar to the calls nearly 25 years ago for a ban involving recombinant DNA. Global legislative efforts in this field have been characterised by many legal, ethical and practical challenges, stemming from conflicting views regarding human embryonic research and cloning. National policy and regulatory developments have primarily been shaped by different understandings of relevant scientific objectives, as well as those relating to the moral and legal status of the human embryo, which have been used to justify or limit a range of permissible activities. Legal obscurity in this field, a consequence of inconsistent or vague legislative responses at a national and international level, leads to negative results, which include, among others, ethical violations; lack of collaboration and co-operation among researchers across national borders; stunted scientific progress; lack of public trust in stem cell research; proliferation of untested ‘stem cell therapies’; and safety issues. The purpose of this article is to explore the legal regulation of stem cell research and therapy globally, by comparing the permissibility of specific stem cell research activities in 35 selected jurisdictions, followed by a comparison of the regulatory approaches with regard to stem cell-based products in the European Union and the USA. A clearer understanding of the global regulatory framework will assist in formulating more effective legal responses at a national level and in navigating the uncertainties and risks associated with this complex and evolving scientific field.

  19. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Ohi, S.

    Departments of Biochemistry &Molecular Biology, Genetics &Human Genetics, Pediatrics &Child Long-duration space missions require countermeasures against severe/invasive disorders in astronauts that are caused by space environments, such as hematological/cardiac abnormalities, bone/muscle losses, immunodeficiency, neurological disorders, and cancer. Some, if not all, of these disorders may be amenable to hematopoietic stem cell therapy and gene therapy. Growing evidence indicates that hematopoietic stem cells (HSCs) possess extraordinary plasticity to differentiate not only to all types of blood cells but also to various tissues, including bone, muscle, skin, liver and neuronal cells. Therefore, our working hypothesis is that the hematopoietic stem cell-based therapy, herein called as the hematopoietic stem cell therapy (HSCT), might provide countermeasure/prevention for hematological abnormalities, bone and muscle losses in space, thereby maintaining astronauts' homeostasis. Our expertise lies in recombinant adeno-associated virus (rAAV)-mediated gene therapy for the hemoglobinopathies, -thalassemia and sickle cell disease (Ohi S, Kim BC, J Pharm Sci 85: 274-281, 1996; Ohi S, et al. Grav Space Biol Bull 14: 43, 2000). As the requisite steps in this protocol, we established procedures for purification of HSCs from both mouse and human bone marrow in 1 G. Furthermore, we developed an easily harvestable, long-term liquid suspension culture system, which lasts more than one year, for growing/expanding HSCs without stromal cells. Human globin cDNAs/gene were efficiently expressed from the rAAVs in the mouse HSCs in culture. Additionally, the NASA Rotating Wall Vessel (RWV) culture system is being optimized for the HSC growth/expansion. Thus, using these technologies, the above hypothesis is being investigated by the ground-based experiments as follows: 1) -thalassemic mice (C57BL/6-Hbbth/Hbbth, Hbd-minor) are transplanted with normal isologous HSCs to correct the

  20. Cell therapy for the treatment of lower limb lymphedema. Case report

    International Nuclear Information System (INIS)

    Goicoechea Diaz, Pedro; Hernandez Ramirez, Porfirio; Artaza Sanz, Heriberto

    2010-01-01

    Although lymphedema is a common disabling disease causing significant morbidity for affected patients, treatment for this condition remains limited and largely ineffective. Some reported data suggest that some bone-marrow derived cells may play a role in lymphangiogenesis. It appears that blood vessels and lymphatic vessels might use the same population of cells for vasculogenesis and lymphangiogenesis. Therefore, adult stem cell therapy could be a new useful strategy for the treatment of lymphedema. We report a resolution of a severe lower limb bilateral lymphedema after implantation of autologous adult stem cells derived from bone marrow. As far as we know, this is the first reported case with chronic lower limb lymphedema treated successfully with autologous cell therapy. This procedure is a low-cost, relatively simple and easy to perform option that opens new ways for the treatment of lymphedema

  1. Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells.

    Science.gov (United States)

    Masiuk, Katelyn E; Brown, Devin; Laborada, Jennifer; Hollis, Roger P; Urbinati, Fabrizia; Kohn, Donald B

    2017-09-06

    Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 10 8 to 1 × 10 9 CD34 + cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34 + cells uses LV inefficiently, because the majority of CD34 + cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34 + CD38 - cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34 + CD38 - cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34 + purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34 + CD38 - cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38 + cells. Importantly, LV modification and transplantation of IB-purified CD34 + CD38 - cells/non-modified CD38 + cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34 + cells, while utilizing ∼7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  2. Role of stem cells in tumor initiation, metastasis formation and their use in cancer therapy

    International Nuclear Information System (INIS)

    Altaner, C.; Altanerova, V.

    2010-01-01

    This review considers recent advances in the stem cell field focusing on the challenges and opportunities for their use in clinical practice. Various kinds of stem cells and their roles in the human organism are in the review described. Attention is given to the role of mesenchymal stem cells as a potential tool in regenerative medicine. The origin and consequences of existence of tumor-initiating cells known as cancer stem cells is discussed also in context of metastasis formation. It seems that tumor-initiating cells might be responsible for resistance to many conventional cancer therapies, which might explain the limitations of these therapeutic modalities. Furthermore, the review focuses to tumor homing property of adult mesenchymal (stromal) stem cells. The feasibility of mesenchymal stem cells isolation from human adipose tissue, their genetic modifications with suicide genes together with ability to find tumor in the organism make them an attractive vehicle for cancer therapy without systemic toxicity. Published achievements from our laboratory in stem cell-based gene cancer therapy are shortly summarized. Generally, it is believed that the stem cell therapies might be ideal future treatment modality for inherited, degenerative diseases and in curing human malignancies as well. (author)

  3. Psychological therapies for sickle cell disease and pain.

    Science.gov (United States)

    Anie, Kofi A; Green, John

    2015-05-08

    Sickle cell disease comprises a group of genetic blood disorders. It occurs when the sickle haemoglobin gene is inherited from both parents. The effects of the condition are: varying degrees of anaemia which, if severe, can reduce mobility; a tendency for small blood capillaries to become blocked causing pain in muscle and bone commonly known as 'crises'; damage to major organs such as the spleen, liver, kidneys, and lungs; and increased vulnerability to severe infections. There are both medical and non-medical complications, and treatment is usually symptomatic and palliative in nature. Psychological interventions for individuals with sickle cell disease might complement current medical treatment, and studies of their efficacy have yielded encouraging results. This is an update of a previously published Cochrane Review. To examine the evidence that psychological interventions improve the ability of people with sickle cell disease to cope with their condition. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and the Internet, handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 17 February 2015. All randomised or quasi-randomised controlled trials comparing psychological interventions with no (psychological) intervention in people with sickle cell disease. Both authors independently extracted data and assessed the risk of bias of the included studies. Twelve studies were identified in the searches and seven of these were eligible for inclusion in the review. Five studies, involving 260 participants, provided data for analysis. One study showed that cognitive behaviour therapy significantly reduced the affective component of pain (feelings about pain), mean difference -0.99 (95% confidence interval -1.62 to -0.36), but

  4. Mesenchymal Stem Cell Therapy in Diabetes Mellitus: Progress and Challenges

    OpenAIRE

    El-Badri, Nagwa; Ghoneim, Mohamed A.

    2013-01-01

    Advanced type 2 diabetes mellitus is associated with significant morbidity and mortality due to cardiovascular, nervous, and renal complications. Attempts to cure diabetes mellitus using islet transplantation have been successful in providing a source for insulin secreting cells. However, limited donors, graft rejection, the need for continued immune suppression, and exhaustion of the donor cell pool prompted the search for a more sustained source of insulin secreting cells. Stem cell therapy...

  5. In vitro evaluation of the effect of linezolid and levofloxacin on Bacillus anthracis toxin production, spore formation and cell growth.

    Science.gov (United States)

    Head, Breanne M; Alfa, Michelle; Sitar, Daniel S; Rubinstein, Ethan; Meyers, Adrienne F A

    2017-02-01

    Owing to its ability to form spores and toxins, Bacillus anthracis is considered a bioterror agent. Although current therapeutic strategies can be effective, treatment does not prevent sporulation and toxin production. To quantify the combined effect of a protein synthesis inhibitor and a bactericidal agent on B. anthracis toxin production, sporulation and cell growth. Susceptibility and synergy titrations were conducted on B. anthracis Sterne and 03-0191 strains using linezolid and levofloxacin. The effect of antibiotic exposure on cell viability was evaluated using a continuous medium replacement model. In vitro static models were used to study the effect of linezolid and levofloxacin on sporulation and toxin production. Spores were quantified using the heat shock method. Toxin was quantified via commercial ELISA. Synergy titrations indicated that the combination was synergistic or indifferent; however, in all models antagonism was observed. In the spore model, linezolid resulted in the lowest sporulation rates, while combination therapy resulted in the highest. In the toxin model, linezolid prevented toxin production altogether. This study advances our understanding of the effects of combination therapy on B. anthracis infection. Used alone, linezolid therapy abolishes toxin production and reduces sporulation. These results suggest that studies using a step-wise approach using linezolid initially to stop sporulation and toxin production followed by levofloxacin to rapidly kill vegetative B. anthracis can be recommended. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Oral beta-glucan adjuvant therapy converts nonprotective Th2 response to protective Th1 cell-mediated immune response in mammary tumor-bearing mice.

    Directory of Open Access Journals (Sweden)

    Gordon D Ross

    2007-06-01

    Full Text Available Beta (1-3-D-glucans were identified almost 40 years ago as biological response modifiers that stimulated tumor rejection. In vitro studies have shown that beta-glucans bind to a lectin domain within complement receptor type 3 (CR3, or to, more recently described dectin-1 a beta-glucan specific receptor, acting mainly on phagocytic cells. In this study, we assessed the intracellular cytokine profiles of peripheral blood lymphocytes from mice bearing mammary tumors receiving i.v. anti-tumor mAbs combined or not with whole glucan particle suspension given orally (WGP, 400 microg every 24 hours. The proportions of T cells producing IL-4 and IFNgamma were determined by flow cytometry. The proportion of T cells producing IL-4 was significantly higher in tumor-bearing mice not receiving beta-glucan-enhanced therapy. Conversely, T cells from mice undergoing beta-glucan-enhanced therapy showed increased production of the Th1 cytokine IFNgamma. The switch from a Th2 to a Th1 response after WGP therapy was possibly mediated by intestinal mucosal macrophages releasing IL-12.

  7. Adoptive Cell Therapies for Glioblastoma

    Directory of Open Access Journals (Sweden)

    Kevin James Bielamowicz

    2013-11-01

    Full Text Available Glioblastoma (GBM is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard-of-care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients(1. Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly self, it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer (LAK cells, natural killer (NK cells, cytotoxic T lymphocytes (CTL, and transgenic chimeric antigen receptor (CAR- or αβ T cell receptor (TCR grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system towards the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts.

  8. Adoptive Cell Therapies for Glioblastoma

    Science.gov (United States)

    Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

    2013-01-01

    Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiothe