Switchable targeting of solid tumors by BsCAR T cells.

Abstract

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on (1) ankyrin repeat (DARPin)-barnase proteins and (2) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2+ ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.

• Authors: Alexey V Stepanov, Roman S Kalinin, Victoria O Shipunova, Ding Zhang, Jia Xie, Yuri P Rubtsov, Valeria M Ukrainskaya, Alexey Schulga, Elena V Konovalova, Dmitry V Volkov, Igor A Yaroshevich, Anastasiia M Moysenovich, Alexey A Belogurov Jr, Hongkai Zhang, Georgij B Telegin, Alexandr S Chernov, Mikhail A Maschan, Stanislav S Terekhov, Peng Wu, Sergey M Deyev, Richard A Lerner, Alexander G Gabibov, Sidney Altman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 46 Pg. e2210562119 (Nov 16 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 36343224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Antigen, T-Cell
• Antigens, Neoplasm

Topics

• Humans
• T-Lymphocytes
• Receptors, Antigen, T-Cell
• Immunotherapy, Adoptive
• Neoplasms (metabolism)
• Antigens, Neoplasm