Cytokine IL-36γ Improves CAR T Cell Functionality and Induces Endogenous Anti-Tumor Response

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable responses in B cell malignancies. However, many patients suffer from limited response and tumor relapse due to lack of persisting CAR T cells and immune escape. These clinical challenges have compromised the long-term efficacy of CAR T cell therapy and call for the development of novel CAR designs. We demonstrated that CAR T cells secreting a cytokine interleukin-36γ (IL-36γ) showed significantly improved CAR T cell expansion and persistence, and resulted in superior tumor eradication compared to conventional CAR T cells. The enhanced cellular function by IL-36γ was mediated through an autocrine manner. In addition, activation of endogenous antigen-presenting cells (APCs) and T cells by IL-36γ aided the formation of a secondary anti-tumor response which delayed the progression of antigen-negative tumor challenge. Together, our data provide preclinical evidence to support the translation of this design for an improved CAR T cell–mediated anti-tumor response.