嵌合抗原受体
癌症研究
T细胞
过继性细胞移植
细胞
免疫疗法
细胞疗法
医学
T细胞受体
免疫学
化学
免疫系统
生物化学
作者
Jiemiao Hu,Qing Yang,Wendong Zhang,Hongwei Du,Yuhui Chen,Qingnan Zhao,Long Dao,Xueqing Xia,Fowlkes Natalie Wall,Zhongting Zhang,Kris Michael Mahadeo,Richard Görlick,Scott Kopetz,Gianpietro Dotti,Shulin Li
标识
DOI:10.1136/jitc-2021-003633
摘要
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.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.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.This novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.
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