CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors

Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206− M1 macrophages and NKG2D+ NK cells increased in number, whereas Tregs, suppressive CD103+ DCs, and M2 macrophages decreased, suggesting that “iIL18 TRUCKs” can be used to sensitize large solid tumor lesions for successful immune destruction. [Display omitted] •CAR T cells releasing IL-18 upon CAR stimulation convert to Tbethigh FoxO1low T cells•IL-18 TRUCK treatment induces a Th1 acute phase response in the tumor•IL-18 TRUCK cells improve survival of mice with advanced pancreatic and lung tumors Chmielewski and Abken engineer IL-18-secreting CAR T cells (IL-18 TRUCKs) to convert cytotoxic T cells to Tbethigh FoxO1low and shape a pro-inflammatory environment in advanced tumors.