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

Abstract

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.

Understanding clinical development of chimeric antigen receptor T cell therapies

“…However, as supported in the literature, we included the majority of all CAR T-cell clinical trials that were performed in Canada, Europe and United States [7][8][9].…”

“…In addition, overviews of CAR T-cell clinical trials from the literature and their trial numbers were compared with those in our data file [7,8]. 14 clinical trials from literature that were not present in the data file were added to the remaining 92 clinical trials from the queries, resulting in the final 106 clinical trials with CAR T cells in Canada, Europe and in the United States ( Figure 1).…”

“…Chimeric antigen receptor (CAR) T cells are a GCT product subtype with promising efficacy in cancer treatment that have been tested in many clinical trials globally [6][7][8]. CARs generally contain two domains, an antigen-recognition and a signaling domain, inserted by gene transfer, through which the T cells can specifically recognize and attack unwanted target cells.…”

Clinical Development and Manufacture of Chimeric Antigen Receptor T cells and the Role of Leukapheresis

“…46,66,67 CD19 is present on B cell leukaemias and lymphomas as well as on healthy B cells, but not on haematopoietic stem cells of other tissues. In one trial, a total of 30 adults and children with acute lymphoblastic leukaemia were given CAR T cell therapy against CD19.…”

Chimeric antigen receptor–engineered natural killer and natural killer T cells for cancer immunotherapy

“…First-generation CARs consisted of scFv and the T cell receptor CD3ζ chain without the presence of any co-stimulatory domains. Second generation CARs included a co-stimulatory molecule, such as CD28 and 4-1BB, in the intracellular domain (1, 2), which greatly enhanced expansion and persistence of T cell activation (3). The third generation included two co-stimulatory molecules which also enhanced activation, proliferation, and survival of T cells, thereby improving efficacy (4).…”