Switchable targeting of solid tumors by BsCAR T cells

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, Hongkai Zhang, Georgij B. Telegin, Alexandr S. Chernov, Mikhail A. Maschan, Stanislav S. Terekhov, Peng Wu, Sergey M. DeyevRichard A. Lerner, Alexander G. Gabibov, Sidney Altman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere2210562119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number46
DOIs
StatePublished - Nov 15 2022
Externally publishedYes

Keywords

  • CAR T cells
  • DARPins
  • barnase–barstar interaction
  • solid tumors
  • switchable adoptive immunotherapy (SAI)

ASJC Scopus subject areas

  • General

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