Establishing guidelines for CAR-T cells: challenges and considerations

SCIENCE CHINA Life Sciences SPECIAL TOPIC: Fighting cancer with armed T cells • REVIEW • April 2016 Vol.59 No.4: 333–339 doi: 10.1007/s11427-016-5026-5 Establishing guidelines for CAR-T cells: challenges and considerations Wei Wang1*, Di-Yuan Qin1, Bing-Lan Zhang1, Wei Wei2, Yong-Sheng Wang1* & Yu-Quan Wei1 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; 2 Department of Emergency, West China Hospital, Sichuan University, Chengdu 610041, China Received December 22, 2015; accepted January 17, 2016; published online March 9, 2016 T cells, genetically modified by chimeric antigen receptors (CAR-T), are endowed with specificity to a desired antigen and are cytotoxic to cells expressing the targeted antigen. CAR-T-based cancer immunotherapy is a promising therapy for curing hematological malignancy, such as acute lymphoid leukemia, and is promising for extending their efficacy to defeat solid tumors. To date, dozens of different CAR-T cells have been evaluated in clinical trials to treat tumors; this necessitates the establishment of guidelines for the production and application of CAR-T cells. However, it is challenging to standardize CAR-T cancer therapy because it involves a combination of gene therapy and cell therapy. In this review, we compare the existing guidelines for CAR-T cells and discuss the challenges and considerations for establishing guidance for CAR-T-based cancer immunotherapy. chimeric antigen receptor, CAR-T cells, guideline, cancer immunotherapy Citation: Wang, W., Qin, D.Y., Zhang, B.L., Wei, W., Wang, Y.S., and Wei, Y.Q. (2016). Establishing guidelines for CAR-T cells: challenges and considerations. Sci China Life Sci 59, 333–339. doi: 10.1007/s11427-016-5026-5 INTRODUCTION Immunotherapy has long been a research focus for cancer treatment. The adoptive transfer of immune cells is efficacious for inhibiting the growth and invasion of cancer cells (Rosenberg et al., 2008). Cytotoxicity elicited by effector cells contributes to tumor-killing efficacy. By producing lymphokine-activated killers, cytokine-induced killers, and selecting and expanding tumor-infiltrating lymphocytes, researchers have developed and significantly advanced the application of cancer immunotherapy, including substantially enhancing the quality of effector cells, for sophisticated clinical utilization. Since the end of 1990s (Gilham et al., 2012; Gross et al., 1989; Kuwana et al., 1987), T *Corresponding author (email: ; ) lymphocytes have been genetically equipped with chimeric antigen receptors (CAR), by which the specificity of T cells can be modulated to a desired antigen. Distinct from unmodified effector T cells, CAR-modified T (CAR-T) cells exert tumor-killing responses in a human leukocyte antigen-independent manner. Another effector cells, Natural Killer cells (NK) are redirected by CARs (Li et al., 2015). With the development of the first generation CAR construct through the third generation, various CAR-T cells have been generated to treat different tumors. Currently, more than 50 clinical trials involving CAR-T cells to treat cancers are under phase I/II studies. Notably, CAR-T cells with CD19 specificity showed high efficacy for the treatment of refractory/relapsed hematological malignancies (Brentjens et al., 2013; Grupp et al., 2013; IKalos et al., 2011; Kochenderfer et al., 2010; Porter et al., 2011). CAR-T-based cancer © The Author(s) 2016. This article is published with open access at link.springer.com life.scichina.com link.springer.com 334 Wang, W., et al. Sci China Life Sci immunotherapy, along with monoclonal antibodies of immune checkpoints, led a scientific breakthrough in 2013 (Couzin-Frankel, 2013). NECESSITY OF GUIDELINES FOR CAR-T CELLS It is widely accepted that medical drugs should be regulated by specific administration under set guidelines. Guidelines for medical drugs should be developed by regulation departments as well as experienced researchers and physicians. Well-established guidelines warrant the quality of the product and guarantee the preliminary requirement for safe and efficacious applications. Importantly, guidelines support the advancement of related techniques and accelerate the application of regulated products. For CAR-T cells, guidance from administration under set guidelines is essential. Different academic institutions generated CAR-T cells with their own modifications, leading to variations in the phenotype, biological potency, and other characteristics. Therefore, it is important to establish guidelines for mandating preliminary requests for CAR-T cells and the production process. Indeed, it is challenging to establish well-accepted guidelines for the entire CAR-T industry because clinical data of CAR-T cells with distinct phenotypes or production methods often show equal efficacy. The guidelines, therefore, are regulations describing the minimal and fundamental criteria for production, in-process releasing tests, and certificate analysis (Gee, 2015). EXISTING GUIDELINES SUITABLE FOR CAR-T CELLS Unlike traditional “off-the-shelf” drugs, CAR-T cells have unique features. CAR-T cells are somatic cells that are under the regulation guidelines for cell therapy. Their genetic modification categorizes them gene therapy products. To date, more than 70 clinical trials have been registered, with 46 trials in the United States and 16 trials in China (data according to www.clinicaltrials.gov). These CAR-T cells must be regulated by domestic guidelines. The Food and Drug Administration (FDA) in United States has classified CAR-T cells as 351 biological products and regulates them through “Considerations for the design of early-phase clinical trials of cellular and gene therapy products” and “Guidance for industry: preclinical assessment of investigational cellular and gene therapy products”, dated November 2013, direct by the Office of Cellular, Tissue, and Gene Therapies in the Center for Biologics Evaluation and Research. Additionally, CAR-T cells should meet the criteria for chemistry, manufacturing, control (CMC) information following the released guidance “Guidance for FDA reviewers and sponsors: content and review of chemistry, manufacturing, and control (CMC) information for human somatic cell therapy investigational new drug appli- April (2016) Vol.59 No.4 cations (INDs)”; dated April 2008 and “Guidance for FDA reviewers and sponsors: content and review of chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug applications (INDs); dated April 2008”. These regulations direct the manufacturing, in-process control, release testing, and quality control of the CAR-T cells. In Europe, the medical administration is regulated by the European medicines agency (EMA). The issued guideline “Guideline on quality, non-clinical and clinical aspects of medicinal products containing g (...truncated)