Immunotherapy

Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells

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Abstract

Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19+ leukemia or mesothelin+ solid tumors respectively in vitro and in vivo. In a patient with relapsed B-cell acute lymphoblastic leukemia, a single dose of 5 × 104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling can contribute to the efficacy of CAR T cells. Further clinical trials are warranted to establish the safety and efficacy of this approach.

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Acknowledgements

We sincerely thank Dr Robert Weinkove at Malaghan Institute of Medical Research for his help in revising the manuscript. This study was supported by National Natural Science Foundation of China (81522002), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19030205), the Natural Science Fund for Distinguished Young Scholars of Guangdong Province (2014A030306028), the Guangdong Provincial Applied Science and Technology Research& Development Program (2016B020237006), the Guangdong Provincial Outstanding Young Scholars Award (2014TQ01R068), the Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province, (2015B020227003, 2014B020225005, 2016B030229006), the Guangdong Provincial Research and Commercialization Program (2014B090901044), and the Guangzhou Science Technology and Innovation Commission Project (201504010016). A patent application has been filed for the TLR2 incorporated CAR vector, and PL and YL are listed as authors on this application. The clinical trial is being sponsored by Guangdong Zhaotai Invivo Biomedicine Co. Ltd. and Hunan Zhaotai Yongren Medical Innovation Ltd.

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Correspondence to X Du or P Li.

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Supplementary Information accompanies this paper on the Leukemia website

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