The growing world of CAR T cell trials: a systematic review

Abstract

In recent years, cancer treatment involving adoptive cell therapy with chimeric antigen receptor (CAR)-modified patient's immune cells has attracted growing interest. Using gene transfer techniques, the patient's T cells are modified ex vivo with a CAR which redirects the T cells toward the cancer cells through an antibody-derived binding domain. The T cells are activated by the CAR primary signaling and costimulatory domains. Such "second generation" CAR T cells induced complete remission of B cell malignancies in the long-term. In this fast-moving field with a growing number of engineered T cell products, we list about 100 currently ongoing trials here that involve CAR T cells targeting hematopoietic malignancies and solid cancer. Major challenges in the further development of the therapy are briefly discussed.

Keywords: Adoptive cell therapy; CAR; Chimeric antigen receptor; Clinical trial; T cell.

Fig. 1

Families of CARs. a The prototype CAR consists in the extracellular domain of a single chain fragment of variable region (scFv) antibody and a spacer, typically the IgG1 CH2CH3, and in the intracellular domain of the CD3ξ signaling chain providing the primary signal (1st generation CAR). The CAR may harbor one costimulatory or two costimulatory domains in addition to the CD3ξ chain (2nd generation CAR, 3rd generation CAR, respectively). Other signaling chains and various combinations are also described. TRUCK T cells (4th generation) are CAR T cells with CAR inducible release of a “payload” which is a transgenic product, e.g., a cytokine such as IL-12 [4]. b The inhibitory CAR (iCAR) harbors a suppressing instead of an activating signal domain. c Split CAR systems consist of two CARs in the same T cell; the CARs recognize different antigens by their individual scFvs, one CAR providing the CD3ξ signal, the other CAR the costimulatory signal required for full T cell activation (costimulatory CAR) or an suppressor signal to suppress T cell activity (inhibitory CAR). d The switch receptor harbors the PD-1 extracellular domain, or any other receptor for an inhibitory ligand, which is linked to the CD28 costimulatory intracellular domain, thereby switching engagement of an inhibitory ligand into an activating signal