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The third-generation anti-CD30 CAR T-cells specifically homing to the tumor and mediating powerful antitumor activity

Zhang Shangkun,Gu Chaojiang,Huang Lifang,Wu Han,Shi Jiangzhou,Zhang Zijian,Zhou Yong,Zhou Jingjiao,Gao Yang,Liu Jiaxing,Leng Yingqi,Liu Xiyu,Zhang Qinxing,Huang Liang,Tong Xiqin,Young Ken H.,Li Jiapeng,Zhu Haichuan,Zhang Tongcun

CAR T-cell therapy is well tolerated and effective in patients with Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). However, even second- generation anti-CD30 CAR T-cells with CD28 (28z) costimulatory domains failed to achieve the desired rate of complete responses. In the present study, we developed second-generation (CD28z) and third-generation (CD28BBz) CAR T-cells targeting CD30 and investigated their efficacy in vitro and in vivo. Both of CD28z and CD28BBz anti-CD30 CAR T cells were similar regarding amplification, T cell subsets distribution, T cell activity, effector/memory and exhaustion. However, we found that the 28BBz anti-CD30 CAR T-cells persist long-term, specifically homing to the tumor and mediating powerful antitumor activity in tumor xenograft models. Subsequently, we also demonstrated that the third generation anti-CD30 CAR T-cells have miner side effects or potential risks of tumorigenesis. Thus, anti-CD30 CAR T-cells represent a safe and effective treatment for Hodgkin lymphoma.