Strategies for modifying the chimeric antigen receptor (CAR) to improve safety and reduce toxicity in CAR T cell therapy for cancer

Immune cell therapy with chimeric antigen receptor (CAR) T cells, which has shown promising efficacy in patients with some hematologic malignancies, has introduced several successfully approved CAR T cell therapy products. Nevertheless, despite significant advances, treatment with these products has major challenges regarding potential toxicity and sometimes fatal adverse effects for patients. These toxicities can result from cytokine release or on-target off-tumor toxicity that targets healthy host tissue following CAR T cell therapy. The present study focuses on the unexpected side effects of targeting normal host tissues with off-target toxicity. Also, recent safety strategies such as replacing or adding different components to CARs and redesigning CAR structures to eliminate the toxic impact of CAR T cells, including T cell antigen coupler (TAC), switch molecules, suicide genes, and humanized monoclonal antibodies in the design of CARs, are discussed in this review.