RT Journal Article SR Electronic T1 Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e003633 DO 10.1136/jitc-2021-003633 VO 10 IS 1 A1 Hu, Jiemiao A1 Yang, Qing A1 Zhang, Wendong A1 Du, Hongwei A1 Chen, Yuhui A1 Zhao, Qingnan A1 Dao, Long A1 Xia, Xueqing A1 Natalie Wall, Fowlkes A1 Zhang, Zhongting A1 Mahadeo, Kris A1 Gorlick, Richard A1 Kopetz, S A1 Dotti, Gianpietro A1 Li, Shulin YR 2022 UL http://jitc.bmj.com/content/10/1/e003633.abstract AB 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.