Cytokine-Engineered Chimeric Antigen Receptor-T Cell Therapy: How to Balance the Efficacy and Toxicity

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the paradigm in hematological malignancies. However, its efficacy in treating solid tumors remains limited because the immunosuppressive tumor microenvironment (ITME) seriously blocks T cell activation, infiltration, and proliferation. Cytokines, driving potent assisted function by enhanced T cell expansion, persistence, and direct tumor cell killing, have long been acknowledged as promising candidates combined with CAR-T cells to improve treatment outcomes. Despite their preclinical success, significant toxicity occurs in up to one-third of patients induced by powerful immune-mediated cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In these cases, the risk-benefit unbalance is less advantageous for advanced cancer therapies, appealing for a profound understanding of pathophysiological mechanisms of CRS and ICANS, as well as improved management of regulating cytokine production. In this review, we first provide an overview of activation and cytotoxic mechanisms of CAR-T cells. Second, obstacles to CAR-T cells in the ITME are introduced in detail. Third, the advanced design of CAR-T engineered cytokines, coupled with current research progress, is described. Furthermore, pathophysiology and clinical features of CRS and ICANS are described in detail. Lastly, prevention and/or intervention approaches of the two above-mentioned toxicities are emphasized both for developing novel therapeutics and maximizing the benefit of patients.