Chmielewski and Abken showed that cytokine IL-18 can promote cytotoxic T cells to express a Tbethigh FoxO1low signature characteristic of effector cells not easily exhausted. After cleverly engineering CAR T cells to secrete IL-18 upon CAR stimulation (preventing systemic cytokine release), they observed prolonged survival in mice with large, established pancreatic or lung cancer. Consistent with an acute inflammatory state, NK cells, activated DCs, and pro-inflammatory macrophages increased and Tregs and pro-tumor macrophages decreased.

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-bet(high) FoxO1(low) 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.

Author Info: (1) Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de

Author Info: (1) Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany. Electronic address: markus.chmielewski@uk-koeln.de. (2) Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Dept. I of Internal Medicine, University Hospital Cologne, Cologne, Germany.

Less