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 Jiemiao Hu
A1 Qing Yang
A1 Wendong Zhang
A1 Hongwei Du
A1 Yuhui Chen
A1 Qingnan Zhao
A1 Long Dao
A1 Xueqing Xia
A1 Fowlkes Natalie Wall
A1 Zhongting Zhang
A1 Kris Mahadeo
A1 Richard Gorlick
A1 S Kopetz
A1 Gianpietro Dotti
A1 Shulin Li
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.