The Pleiotropic Roles of Cytokines in Chimeric Antigen Receptor T-cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell–associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.