The landscape of CAR T-cell therapy in the United States and China: A comparative analysis.

The clinical trials of CAR T-cell therapy are growing fast in recent years, and most of the trials are initiated by sponsors from the United States and China. Exhibiting the distinctions between the clinical trials in the two countries is of great value for understanding the panorama of CAR T-cell clinical trials and forecasting the future of this promising therapy. We analyzed the critical elements of 289 clinical trials posted on the clinicaltrials.gov website by sponsors from the two countries and evaluated the efficacy data in available 50 published CAR T-cell studies. Our analysis shows that China has become the country with the largest number of CAR-T cell clinical trials by the end of 2017, while overall subject sample size and study center numbers are still larger, and the design of the clinical trials is more cautious in the United States. There are obvious differences between the two countries in CAR-targeted antigens in solid tumors and genetic modifications besides CARs for enhancing the potency of CAR T-cells. Although the currently available response rates are promising in both countries, it is inexpedient to conclude that the clinical efficacy is comparable between the two countries considering the smaller patient sample sizes and discrete distribution of median cell doses in China. And finally, the flexible regulatory regime of cell therapy in China, which expedites the bursting of CAR T-cell therapy, is also firstly introduced in our study.

Sipuleucel-T for the treatment of prostate cancer: novel insights and future directions.

Sipuleucel-T, an autologous cellular immunotherapy manufactured from antigen-presenting cells primed to recognize prostatic acid phosphatase, was the first immunotherapy product approved by the US FDA. It was approved for men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer after it was shown to provide a survival advantage. Additional studies have examined its use in other clinical settings and in combination with other approved and investigational immunotherapy agents. This review will discuss the pivotal trials leading to approval, will outline some of the biomarkers associated with its efficacy and will review some of the ongoing combination strategies. Maximizing the efficacy of sipuleucel-T through better patient selection or through combination approaches remains the challenge of the future.

Regulation of adoptive immunotherapy.

Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells has provided a major breakthrough in the treatment of hematological malignancies. In Japan, it is expected that CD19 CAR-T cell therapy will be introduced earlier in clinical B cell malignancy settings and/or that a novel CAR-T cell therapy will be developed for non-B cell malignancies. The "Act on the Safety of Regenerative Medicine" and the "Revised Pharmaceutical Affairs Act" were promulgated in 2014. Both Acts were very important to the introduction and development of CAR-T therapy in Japan. "Specified cell products" produced according to the former Act can be used in clinical research projects, while "regenerated medical products" produced according to the latter Act can be used in clinical trials, having been launched on the market. In this chapter, we will summarize the regulations pertaining to adoptive immunotherapy on the basis of these two essential Acts.

[CAR-T cells gene therapy medicines: Regulatory status and pharmaceutical circuits in Europe and France]. / Les médicaments de thérapie génique CAR-T cells : statuts réglementaires et circuits pharmaceutiques en Europe et en France.

CAR-T cells belong to a new class of biological medicines, referred to as Advanced Therapy Medicinal Products (ATMPs). Despite the cellular component, according to the regulatory definition, CAR-T cells are gene therapy medicines, a sub-category of ATMPs, since their therapeutic effect is the result of their genetic modification. The specificity and the complexity of these innovative drugs have required a complete reorganization of the hospital and pharmaceutical circuits, from the cell collection to the drug administration to the patient. Indeed, increased interaction and collaboration between different healthcare professionals is essential in order to guarantee the quality and safety of these innovative medicines.

[CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations]. / CAR-T cells : comment le registre de l'EBMT monitore les activités en Europe, identifie les contraintes et prépare l'évolution des régulations.

CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells.

[DESCAR-T, a nationwide registry for patient treated by CAR-T Cells in France]. / DESCAR-T, le registre national des patients traités par CAR-T Cells.

CAR-T Cells have opened new doors for cellular immunotherapies and provides new therapeutic options for patients with refractory B-cell malignancies, B-cell acute lymphoblastic leukemia and diffuse large B-cel lymphoma. CAR-T Cells have benefited from an accelerated approval procedure in many countries. Indeed, The French health authorities have approved the specialties Tisacel ® and Axicel ®, but additional data including the use of CAR-T Cells in real life were also mandatory. In regard to the scientific interest of the project, LYSA-LYSARC committed itself to prospectively and retrospectively collect information on patients eligible for CAR-T Cells as required by French health authorities. Other academic cooperating groups (GRAALL, IFM, SFCE, FILO and the scientific society SFGM-TC) were associated to this initiative which aims to build a nationwide CAR-T Cells devoted registry, so-called DESCART (Dispositif d'Enregistrement et Suivi des patients traités par CAR-T cells). DESCAR-T is a real-life multicentric registry set up in French sites qualified for CAR-T Cells treatment. DESCAR-T objective is to describe the use of CAR-T Cells in real life. All paediatric and adult patients with hematological malignancy fulfilling CAR-T Cells approval criteria and for whom a CAR-T Cells therapy has been discussed are included from 1 July 2018. Clinical data are directly collected from medical records and patients are treated according to the centers' routine practices. One of the distinctive features of DESCAR-T is its link with HTA for CAR-T Cells s reimbursement by the French public health system. DESCAR-T is the first national registry promoted by an academic group allowing centralized data collection for both academic and HTA/health authorities' purposes.

[Quality assessment of CAR T-cell activity: Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Mutualisation des outils de qualité pour les cellules CAR-T : recommandations de la Société francophone de greffe de moelle et thérapie cellulaire (SFGM-TC).

CAR T-cells are anti-cancer immunocellular therapy drugs that involve reprogramming the patient's T-cells using a transgene encoding a chimeric antigen receptor (CAR). Although CAR T-cells are cellular therapies, the organization for manufacturing and delivering these medicinal products is in many ways different from the one for hematopoietic cell grafts or donor lymphocyte infusions. The implementation of this innovative therapy is recent and requires close coordination between clinical teams, the therapeutic apheresis unit, the cell therapy unit, the pharmaceutical laboratory, and pharmacy. Apart from the regulatory texts, which are regularly modified, and the specific requirements of each pharmaceutical laboratory, there is currently no guide to help the centers initiating their activity and there is no specific indicator to assess the quality of the CAR T-cell activity in each center. The purpose of the current harmonization workshop is to clarify the regulatory prerequisites warranted for a center to have a CAR T-cell activity and to propose recommendations for implementing quality tools, in particular indicators, and allowing their sharing.

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.

CART manufacturing process and reasons for academy-pharma collaboration.

The success of genetically engineered T-cells modified with a chimeric antigen receptor as an adoptive cell immunotherapy and the subsequent last regulatory approvals of products based on this therapy are leading to a crescent number of both academic and pharmaceutical industry clinical trials testing new approaches of this "living drugs". The aim of this review is to outline the latest developments and regulatory considerations in this field, with a particular emphasis to differences and similarities between academic and industry approaches and the role they should play to coexist and move forward together. To do that, the main considerations for the manufacturing process are firstly discussed, from the chimeric antigen receptor design to final production steps, passing through ex vivo T-cell handling, gene delivery methods, patient´s final product infusion observations or possible associated side effects of this treatment.

Driving the CAR to the Bone Marrow Transplant Program.

PURPOSE OF REVIEW: The US Food and Drug Administration (FDA) approved two commercially available chimeric antigen receptor (CAR) T cell therapies for the treatment of relapsed B cell acute lymphoblastic leukemia (B-ALL) children and young adults less than 25 years of age and non-Hodgkin lymphoma in adults after promising results from early-phase single and multi-institutional clinical trials. In this review, we provide an overview of the practical aspects of a chimeric antigen T cell receptor (CAR-T) program development and the steps necessary for its successful implementation. RECENT FINDINGS: CAR-T therapy is a complex process and poses significant challenges as institutions prepare to deliver this therapy as a standard of care for the eligible patients. It requires a rigorous infrastructure with specific clinical, administrative, and regulatory demands. Institutions that led the clinical trials for CAR-T have adopted various approaches to integrate commercial CAR-T products into their program. Delivering commercial CAR-T cells outside the scope of clinical trials requires careful planning, allocation of resources, and utilization of existing infrastructure. Institutions may need to adapt the existing recommendations and guidelines and tailor them to meet the needs of their program and ensure appropriate financial reimbursement for this expensive but promising immunotherapy.

FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma.

In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% [95% confidence interval (CI), 62-81], with a CR rate of 51% (95% CI, 41-62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI, 8.1 months; not estimable, NE), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI, 1.3-5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a risk evaluation and mitigation strategy.

Réglementations applicables aux CAR-T cells : comment les établissements de santé français peuvent-ils s'organiser pour participer à la production et permettre la délivrance de ces immunothérapies innovantes ?

REGULATORY FRAMEWORK FOR CAR-T CELLS: HOW CAN FRENCH HEALTHCARE PROVIDERS ADAPT THEIR ORGANIZATION TO REQUIREMENTS FOR MANUFACTURING AND DELIVERY OF THESE INNOVATIVE CELL-BASED MEDICINAL PRODUCTS?: More than five years after the first US publications reporting a significant rate of clinical responses in patients with high-risk or advanced CD19+ lymphoid malignancies, access to treatment with CAR-T Cells at European hospitals in general and at French hospitals in particular remains limited. One - and not the least - hurdle lay in the need to set up a complex and unprecedented organization that complies with European regulations on Advanced Therapy Medicinal Products as well as with national (French) regulations. We here review the organizational framework for two situations: delivery and administration of industry-manufactured CAR-T Cells as well as engineering and distribution of CAR-T Cells produced as investigational drugs to be evaluated in the context of clinical research protocols. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.

Rôle du pharmacien hospitalier dans le circuit d'une catégorie de Médicament de Thérapie Innovante : les lymphocytes T exprimant un Récepteur Chimérique à l'Antigène.

ROLE OF THE HOSPITAL PHARMACIST IN THE MANAGEMENT OF A CATEGORY OF ADVANCED THERAPY MEDICINAL PRODUCT: CHIMERIC ANTIGEN RECEPTOR T-CELLS: Chimeric Antigen Receptor T-cells (CART) belongs to a new class of medicine, Advanced Therapy Medicinal Product, such as define by the European Regulation 1394/2007, and more exactly to the category of gene therapy medicinal product. Their status of medicine, as well as genetically modified organisms, imposes a particular circuit at hospital while maintaining a way over the Hospital Pharmacy. The manipulation of genetically modified cells is not usual in pharmacy. It requires, besides the acquisition of new skills, a not insignificant reorganization of the teams and the rooms of the pharmacy as well as an adapted training of the staff. A good communication is essential between the various actors of the circuit. The hospital pharmacist plays a key role in the implementation of a circuit adapted to this new type of medicine. This article aims to identify the roles of the hospital pharmacist and more generally of the pharmacy in the management of CART. We shall detail the specificities of this type of medicine in every stage of the circuit and the adaptations necessary to realize to guarantee the quality and the safety of the treatment by CART. Beyond the implementation of the circuit in the hospital, the pharmacist has an important role to be played in the follow-up of the patients after administration in view of the complexity of the side effects and a certain role in the training of the teams to this new medicine. Cet article fait partie du numéro supplément Les cellules CAR-T : une révolution thérapeutique ? réalisé avec le soutien institutionnel des partenaires Gilead : Kite et Celgene.

Cell and gene therapies at the forefront of innovative medical care: Implications for South Africa.

The fields of cell and gene therapy are moving rapidly towards providing innovative cures for incurable diseases. A current and highly topical example is immunotherapies involving T-cells that express chimeric antigen receptors (CAR T-cells), which have shown promise in the treatment of leukaemia and lymphoma. These new medicines are indicative of the changes we can anticipate in the practice of medicine in the near future. Despite their promise, they pose challenges for introduction into the healthcare sector in South Africa (SA), including: (i) that they are technologically demanding and their manufacture is resource intensive; (ii) that the regulatory system is underdeveloped and likely to be challenged by ethical, legal and social requirements that accompany these new therapies; and (iii) that costs are likely to be prohibitive, at least initially, and before economies of scale take effect. Investment should be made into finding novel and innovative ways to introduce these therapies into SA sooner rather than later to ensure that SA patients are not excluded from these exciting new opportunities.

Considerations pertaining to cell collection and administration of industry-manufactured autologous CAR-T cells, in relation to French healthcare organization and regulations.

Access to treatment with CAR-T Cells at European hospitals in general and at French hospitals in particular remains limited, when compared with the situation that prevails in the USA or in certain Asian countries. Multiple reasons explain why European investigators lag behind their US or Chinese colleagues in this clinical research area. Some of these reasons are related to the European and French regulatory landscapes that hamper the design and rapid implementation of organizational solutions needed for safe and efficient administration of CAR-T Cells. We here identify some of these pressing issues and propose some possible paths to move forward.

Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a new modality for cancer immunotherapy due to their potent efficacy against terminal cancers. CAR-Ts are reported to exert higher efficacy than monoclonal antibodies and antibody-drug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors. CAR-Ts are classified as first-, second- and third-generation, depending on the intracellular signaling domain number of T cell receptors. This review covers the current status of CAR-T research, including basic proof-of-concept investigations at the cell and animal levels. Currently ongoing clinical trials of CAR-T worldwide are additionally discussed. Owing to the lack of existing approved products, several unresolved concerns remain with regard to safety, efficacy and manufacturing of CAR-T, as well as quality control issues. In particular, the cytokine release syndrome is the major side-effect impeding the successful development of CAR-T in clinical trials. Here, we have addressed the challenges and regulatory perspectives of CAR-T therapy.

New Japanese initiatives on stem cell therapies.

Two laws aiming to provide a new legal framework to promote regenerative medicine, while ensuring the efficacy and safety of the treatments, came into effect in Japan on November 25, 2014. The scope of these laws is briefly described here.