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

Abstract

Background Adoptive T-cell transfer has become an attractive therapeutic approach for hematological malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) exhibits 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 ttIL-12 (attIL12) and a cell membrane-Anchored and tumor-Targeted ttIL-12 (attIL12) armed T cells, chimeric antigen receptor-T cells, and T cell receptor-T (TCR-T) cells with each. We compared the safety and efficacy of these armed T cells in treating osteosarcoma patient-derived xenograft tumors and mouse melanoma tumors 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 targeted tumor cells expressing cell-surface vimentin, enriching effector T cell and interferon γproduction in tumors, which in turn stimulates 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. Conclusions This novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.