Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors

Abstract

Abstract Background Adoptive T-cell transfer has become an attractive therapeutic approach for hematologic malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) potent antitumor efficacy against solid tumors, but its clinical application has been stalled because of toxicity. Here, we aimed to develop a safe approach to IL-12 T-cell therapy for eliminating large solid tumors. Methods We generated a cell membrane-anchored IL-12 (aIL12), a tumor-targeted IL-12 (ttIL12), and a cell membrane-anchored and tumor-targeted IL-12 (attIL12) armed T cells, CAR-T cells, and TCR-T cells with each. We compared the antitumor efficacy of these armed T cells in treating osteosarcoma PDX tumors and mouse melanoma tumors, and addressed the safety concerns of IL-12 expressing T cell therapy after intravenous infusions of the armed T cells. Results attIL12-T cell infusion showed remarkable antitumor efficacy in human and mouse large solid tumor models. Mechanistically, attIL12-T cells target tumor cells that express cell-surface vimentin (CSV) and accumulate in tumor sites. Such CSV-attIL12 interaction stimulates effector T cell to produce high levels of inflammatory cytokines (IFNγ, Flt3L, GM-CSF and etc.) only in tumors, which in turn triggers dendritic cell maturation for activating secondary T-cell responses and tumor antigen spreading. Both attIL12- and aIL12-T-cell transfer eliminated peripheral cytokine release and the associated toxic effects due to tumor-specific T cell distribution and compartment-dependent cytokine secretion. Conclusions This novel approach sheds light on the safe application of IL-12–based T-cell therapy for large and heterogeneous solid tumors. Supported by R01 CA200574