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.
Cell reports