%0 Journal Article %A Jiemiao Hu %A Qing Yang %A Wendong Zhang %A Hongwei Du %A Yuhui Chen %A Qingnan Zhao %A Long Dao %A Xueqing Xia %A Fowlkes Natalie Wall %A Zhongting Zhang %A Kris Mahadeo %A Richard Gorlick %A S Kopetz %A Gianpietro Dotti %A Shulin Li %T Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors %D 2022 %R 10.1136/jitc-2021-003633 %J Journal for ImmunoTherapy of Cancer %P e003633 %V 10 %N 1 %X 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 γ production 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.No data are available. %U https://jitc.bmj.com/content/jitc/10/1/e003633.full.pdf