Chimeric autoantibody receptor T cells clonally eliminate B cells producing autoantibodies against IFN-γ
Jhan-Jie Peng, Jing-Ya Ding, Yingxi Xu, Han-Po Shih, You-Ning Lin, Tsai-Yi Wu, Yu-Fang Lo, Chia‐Chi Lo, Chu-Fu Yeh, Chen-Yen Kuo, Kun‐Hua Tu, Shang‐Yu Wang, Wei‐Te Lei, Ting‐Shu Wu, Huang-Shen Lin, Chen‐Hsiang Lee, Wen‐Chi Huang, Yi‐Chun Chen, Yuag-Meng Liu, Zhi-Yuan Shi, Ya-Ting Chang, Ling-Shan Syue, Po‐Lin Chen, Soon-Hian Teh, Chia-Huei Chou, Mao-Wang Ho, Chih-Yu Chi, Ping‐Chih Ho, Cheng‐Lung Ku
Abstract
, and other intracellular pathogens. Current clinical management relies on continuous antimicrobial therapy, with no treatment offering sustained benefits. Here, we developed human chimeric autoantibody receptor (CAAR) T cells targeting autoreactive B cells expressing nAIGA B cell receptors (BCRs) using an IFN-γ receptor-irresponsive IFN-γ variant as bait. By exploiting a mouse model of nAIGA BCR-expressing B cell leukemia, we found that IFN-γ CAAR T cells lack off-target toxicity, including IFN-γ receptor cross-reactive toxicity and Fc-redirected toxicity. IFN-γ CAAR T cells substantially reduced circulating AIGAs secreted from target cells in vivo. Further, IFN-γ CAAR T cells effectively eliminated autoreactive B cells in ex vivo cultures of peripheral blood mononuclear cells from patients with nAIGAs. Together, these results demonstrate that IFN-γ CAAR T cells may be a promising strategy to ameliorate nAIGA-associated infections by eliminating autoreactive B cells.