Cancer Immunotherapy Using Chimeric Antigen Receptor Expressing T-Cells: Present and Future Needs of Clinical Cancer Centers.

Chimeric Antigen Receptor-T cells (CAR-T) are considered novel biological agents, designed to selectively attack cancer cells expressing specific antigens, with demonstrated clinical activity in patients affected with relapsed/refractory B-cell malignancies. In consideration of their complexity, the use of CAR-T requires dedicated clinical setting and health care practitioners with expertise in the selection, treatment, and management of toxicities and side effects. Such issue appears particularly important when contextualized in the rapid progress of CAR-T cell treatment, translating into a constant need of updating and evolution. Moreover, the clinical grade manufacturing of CAR-T cells is complex and implies articulated regulatory and organizational aspects. The main goal of this review is to summarize and provide an accurate analysis of the clinical, logistic, and regulatory requirements of CAR-T cell centers. Finally, we describe a new occupational figure called "CAR-T specialist" devoted to the establishment and coordination of the required facilities and regulatory landscape in the context of cancer centers.

Clinical Tracking of Cell Transfer and Cell Transplantation: Trials and Tribulations.

Cell therapy has provided unprecedented opportunities for tissue repair and cancer therapy. Imaging tools for in vivo tracking of therapeutic cells have entered the clinic to evaluate therapeutic cell delivery and retention in patients. Thus far, clinical cell tracking studies have been a mere proof of principle of the feasibility of cell detection. This review centers around the main clinical queries associated with cell therapy: Have cells been delivered correctly at the targeted site of injection? Are cells still alive, and, if so, how many? Are cells being rejected by the host, and, if so, how severe is the immune response? For stem cell therapeutics, have cells differentiated into downstream cell lineages? Is there cell proliferation including tumor formation? At present, clinical cell tracking trials have only provided information on immediate cell delivery and short-term cell retention. The next big question is if these cell tracking tools can improve the clinical management of the patients and, if so, by how much, for how many, and for whom; in addition, it must be determined whether tracking therapeutic cells in every patient is needed. To become clinically relevant, it must now be demonstrated how cell tracking techniques can inform patient treatment and affect clinical outcomes.

[LEGAL REGULATION OF TRANSPLANTOLOGY AT THE PRESENT STAGE: UKRAINIAN ISSUE AND EXPERIENCE OF FOREIGN STATES].

The objective of the research is to analyze the legal regulation in the transplantology field at the present stage in Ukraine. To address identified challenges, the author investigates the foreign countries experience and suggests ways of improving certain mechanism for legal regulation in the field of organ transplantation and anatomical materials. The empiric material of the study included a wide range of legal instruments regulating this sphere of legal relationships, information regarding the problems of their application, statistics, expert analysis of Ukrainian and foreign researchers. Methodological mechanism of current research includes such methods: systematic, logical and formal, structural-functional, comparative. The research found that the most world's successful model for the organization of transplantation is in Spain. Additionally, the criteria for the reception of such a model are singled out as well as certain aspects of their application in Ukraine are analyzed. Particularly, the most important criteria are: universal and general territorial proliferation of national health systems; relevant economic resources (special attention is paid to the fact that transplantation is not a medicine of luxury, and an adequate compensation to hospitals for transplantation operations should serve as a main economic aspect); an adequate and necessary number of doctors and nurses; the availability of advanced technical options for medical mechanical ventilation (air conditioning of dead bodies). The research led to the following overall findings. Due to the rapid development of medical and biological sciences, there is an urgent need on further investigation of legal, moral and ethical, general medical aspects of transplantation with subsequent proposals for improving legislation in the field of human organs transplantation and other anatomical materials. At the same time, development of appropriate legislation by complex groups of cross-disciplinary specialists and experts (in medicine, biology, law and bioethics) is the key to legal regulation effectiveness.

Development of an in vitro potency assay for human skeletal muscle derived cells.

BACKGROUND: Potency is a quantitative measure of the desired biological function of an advanced therapy medicinal product (ATMP) and is a prerequisite for market approval application (MAA). To assess the potency of human skeletal muscle-derived cells (SMDCs), which are currently investigated in clinical trials for the regeneration of skeletal muscle defects, we evaluated acetylcholinesterase (AChE), which is expressed in skeletal muscle and nervous tissue of all mammals. METHODS: CD56+ SMDCs were separated from CD56- SMDCs by magnetic activated cell sorting (MACS) and both differentiated in skeletal muscle differentiation medium. AChE activity of in vitro differentiated SMDCs was correlated with CD56 expression, fusion index, cell number, cell doubling numbers, differentiation markers and compared to the clinical efficacy in patients treated with SMDCs against fecal incontinence. RESULTS: CD56- SMDCs did not form multinucleated myotubes and remained low in AChE activity during differentiation. CD56+ SMDCs generated myotubes and increased in AChE activity during differentiation. AChE activity was found to accurately reflect the number of CD56+ SMDCs in culture, their fusion competence, and cell doubling number. In patients with fecal incontinence responding to SMDCs treatment, the improvement of clinical symptoms was positively linked with the AChE activity of the SMDCs injected. DISCUSSION: AChE activity was found to truly reflect the in vitro differentiation status of SMDCs and to be superior to the mere use of surface markers as it reflects not only the number of myogenic SMDCs in culture but also their fusion competence and population doubling number, thus combining cell quality and quantification of the expected mode of action (MoA) of SMDCs. Moreover, the successful in vitro validation of the assay proves its suitability for routine use. Most convincingly, our results demonstrate a link between clinical efficacy and the AChE activity of the SMDCs preparations used for the treatment of fecal incontinence. Thus, we recommend using AChE activity of in vitro differentiated SMDCs as a potency measure in end stage (phase III) clinical trials using SMDCs for skeletal muscle regeneration and subsequent market approval application (MAA).

Cell-Based Therapies with T Regulatory Cells.

CD4+CD25highFoxP3+ T regulatory cells (Tregs) are immunodominant suppressors in the immune system. Tregs use various mechanisms to control immune responses. Preclinical data from animal models have confirmed the huge therapeutic potential of Tregs in many immune-mediated diseases. Hence, these cells are now on the road to translation to cell therapy in the clinic as the first clinical trials are accomplished. To date, clinical research has involved mainly hematopoietic stem cell transplantations, solid organ transplantations, and autoimmunity. Despite difficulties with legislation and technical issues, treatment is constantly evolving and may soon represent a valid alternative for patients with diseases that are currently incurable. This review focuses on the basic and clinical experience with Tregs with adoptive transfer of these cells, primarily from clinical trials, as well as on perspectives on clinical use and technical problems with implementing the therapy.

Chapitre 6. Cells? safety in Europe: Towards an ethical safety.

To encourage and maximise the use of human biological material in Europe, the European Commission instigated a main Directive in 2004 (Directive 2004/23/EC), four technical ones in 2006 (Commission Directives 2006/17/EC and 2006/86/EC) and in 2015 (Commission Directives (EU) 2015/565 and (EU) 2015/566). They encourage the donation of tissues and cells for transplant purposes in the safeguard of public health. Another major aim of Directive 2004/23/EC is to guarantee recipients' safety in transplantation. Hence, measures for accreditation of establishments storing, preparing and distributing tissues and cells are required to be implemented in Members States' jurisdictions. In addition, adequate training is required for the personnel directly involved in such activities. Despite the adoption of a ?full legislation,? the EU legal framework for cells cannot be seen as totally harmonized. In this article we first address the issues posed at the European level by the uses of human cells as therapeutic agent with regards to their qualification: body elements? Medicinal product? We study the ways to address these bioethical dilemmas at an EU level. Then we discuss the impact of this qualification in terms of safety through the definition of safety's measures and their limits regarding the directive's scope. We conclude with the emergence of an ?ethical safety?.

A Cell Graft or a Drug? Legal and Practical Aspects of Somatic Cells Application in Graft-Versus-Host Disease Experimental Treatment: The Polish Experience.

INTRODUCTION: Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation and organ transplantation are well-established treatments for different conditions. Graft versus host disease (GvHD) is a major complication in both methods. There has been a rapid increase in the application of nonhematopoietic somatic cells, such as mesenchymal stem cells and regulatory T cells in GvHD experimental therapy. According to current European Union (EU) law, human cells intended for human application can be considered either as cell grafts or as advanced therapy medicinal products (ATMPs). OBJECTIVE, MATERIALS AND METHODS: The aim of the paper is an attempt to answer, based on GvHD experimental treatment data as well as existing EU and Polish law, whether cells cease to be cells (cell grafts) and becomes drugs (ATMPs); if yes, when; and what are the consequences of such situation both for patients as well as for physicians engaged in the treatment process in Poland. RESULTS AND DISCUSSION: Data analysis confirmed the interest in the experimental GvHD cell therapy. In the vast majority of analyzed cases the in vitro culture step in the cell preparation protocols has been foreseen. Therefore, the answer to title question was unambiguous-expanded cells are recognized in EU as ATMPs. In borderline cases, a scientific recommendation by the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) can play an important auxiliary role; however, it is currently neither required by Polish law nor legally binding in Poland.

Regulatory aspects of clinical xenotransplantation.

Xenotransplantation attracted interest from regulatory authorities, particularly after the demonstration of pig-to-human transmission of porcine endogenous retrovirus (1996). This added to the risk of a product, resulting in a Guidance of the US Food and Drug Administration (2003). This addresses the full flow chart in product manufacturing, starting with the designated pathogen-free status of the source animal; and special aspects regarding the recipient like informed consent and monitoring for infectious pathogens. Also archiving of records from the donor and recipient, as well as storage of samples is described. The European Medicines Agency issued a Guideline on xenogeneic cell therapy products (2009). Cell-based medicinal products are subject to specific regulations and directives, which apply also to xenogeneic products: the xenotransplant guidances/guidelines are an addition to these regulations. Noteworthy, acellular products like heart valves and decellularized cornea are not considered a cell therapy product, but rather a medical device with its own regulation. WHO issued relevant documents, especially about safety, and the International Xenotransplantation Association published consensus documents, a.o., addressing preclinical efficacy requirements before entering clinical trials. This manuscript presents an overview of the regulatory framework, with special focus on cell therapy products necause these are expected to reach the market first (i.e., pancreatic islets, hepatocytes and cellularized cornea); major illustrations are from the European situation. Albeit being complex, the regulation of xenotransplant products does not form a block in product development, but rather supports the introduction of efficacious and safe products to meet the medical need.

Business oriented EU human cell and tissue product legislation will adversely impact Member States' health care systems.

The transplantation of conventional human cell and tissue grafts, such as heart valve replacements and skin for severely burnt patients, has saved many lives over the last decades. The late eighties saw the emergence of tissue engineering with the focus on the development of biological substitutes that restore or improve tissue function. In the nineties, at the height of the tissue engineering hype, industry incited policymakers to create a European regulatory environment, which would facilitate the emergence of a strong single market for tissue engineered products and their starting materials (human cells and tissues). In this paper we analyze the elaboration process of this new European Union (EU) human cell and tissue product regulatory regime-i.e. the EU Cell and Tissue Directives (EUCTDs) and the Advanced Therapy Medicinal Product (ATMP) Regulation and evaluate its impact on Member States' health care systems. We demonstrate that the successful lobbying on key areas of regulatory and policy processes by industry, in congruence with Europe's risk aversion and urge to promote growth and jobs, led to excessively business oriented legislation. Expensive industry oriented requirements were introduced and contentious social and ethical issues were excluded. We found indications that this new EU safety and health legislation will adversely impact Member States' health care systems; since 30 December 2012 (the end of the ATMP transitional period) there is a clear threat to the sustainability of some lifesaving and established ATMPs that were provided by public health institutions and small and medium-sized enterprises under the frame of the EUCTDs. In the light of the current economic crisis it is not clear how social security systems will cope with the inflation of costs associated with this new regulatory regime and how priorities will be set with regard to reimbursement decisions. We argue that the ATMP Regulation should urgently be revised to focus on delivering affordable therapies to all who are in need of them and this without necessarily going to the market. The most rapid and elegant way to achieve this would be for the European Commission to publish an interpretative document on "placing on the market of ATMPs," which keeps tailor-made and niche ATMPs outside of the scope of the medicinal product regulation.

FDA oversight of cell therapy clinical trials.

The U.S. Food and Drug Administration applies regulatory flexibility to balance benefits and risks to subjects in cell-therapy clinical trials.

The European hospital exemption clause-new option for gene therapy?

Gene-therapy medicinal products are currently applied to patients enrolled in authorized clinical trials to demonstrate safety and efficacy. Given a positive outcome, marketing authorization can subsequently be achieved via the centralized procedure coordinated by the European Medicines Agency. With Regulation (EC) No. 1394/2007 in force, advanced therapy medicinal products, including gene- and cell-therapy products, can be excepted from the obligation of obtaining a marketing authorization via the centralized procedure under specific conditions (so-called "hospital exemption"). This hospital exemption allows the application of gene-therapy medicinal products prepared on a non-routine basis for an individual patient and used under the exclusive professional responsibility of a medical practitioner. Here, we explain the requirements to be fulfilled in order to fall under this exemption, the implementation of this regulation into the German national legislation, and its impact on gene-therapy product development in the future.

Regulation of cellular therapy in Australia.

Use of cellular products for therapeutic purposes has predominantly been unregulated in Australia until recently. Transplant of haemopoietic progenitor cells (HPC) for bone marrow regeneration is now a routine treatment for many disorders with an established mechanism of facility accreditation. However, other cellular therapies do not have any form of accreditation, are not well evaluated and may be associated with significant risks. On 31 May 2011 the Therapeutic Goods Administration (TGA) implemented a long heralded regulatory biologicals framework for cell and tissue based therapies. The framework currently excludes human HPC, organs for direct transplantation and reproductive materials which are already covered by various forms of existing peer review and accreditation. This new framework is a practical approach for applying regulation based on the risk of the product to the recipient with four classes of product. Class 1 is reserved for the least regulated products and currently does not contain any proposed products. Class 2 will be for minimally manipulated products which will only require manufacturing compliance and evaluation against product and other mandatory standards before entry onto the Australian Register of Therapeutic Goods (ARTG). Class 3 and 4 products will be more than minimally manipulated and these cells and tissues may be used in a non-homologous manner. Class 3 and 4 products will represent a spectrum of risk where Class 4 therapies will represent the highest potential risk to the recipient, with the same requirements for Class 2 approvals but with additional requirements for comprehensive evaluation of a dossier for quality, safety and efficacy of the product. The extent of this quality, safety and efficacy data will depend upon the nature of the product and its associated risks, but will be more comprehensive for Class 4 as opposed to Class 3 products. The only truly contentious feature of this framework is the extremely high cost for dossier evaluation and the puzzling absence of an orphan drug scheme for biologicals.

Access to advanced therapy medicinal products in the EU: where do we stand?

The European Union has a public health strategy and will generally ensure in all its policies and activities a "high level of human health protection". The new Regulation (EC) n 1394/2007 on advanced therapy medicinal products (ATMP), stems from this global policy and aims to harmonise access to the ATMP market. A real will for the harmonisation is clearly expressed in legal texts and enforced in the implementable procedures and requirements. However, several barriers remain. On the one hand, the scope of the ATMP Regulation is limited. On the other hand, Member States benefit from a wide margin of action.

The cell based therapy and the policy implications in India.

The recent scientific development using stem or other differentiated cells has generated great hopes for treatment of various diseases. Major thrust has been given to formulate country specific laws and regulations considering international guidelines to conduct research and clinical applications of "Cell Based Therapy" (CBT) all over the world. Attempts have made in this review to discuss the current policies that are practiced by various countries in the areas related to CBT with special emphasis on CBT related research and development in India. The two major funding agencies of Government of India e.g. Department of Biotechnology (DBT) and Indian Council of Medical Research (ICMR), have jointly formulated the "Guidelines for Stem Cell Research and Therapy" in 2007 which requires update and revision. Based on the review of the current world scenario of CBT research and development, suggestions have been made for the development of a new CBT policy that will help in progress of research and patient treatment in India.