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Switchable targeting of solid tumors by BsCAR T cells

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 r...

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Detalles Bibliográficos
Autores principales: Stepanov, Alexey V., Kalinin, Roman S., Shipunova, Victoria O., Zhang, Ding, Xie, Jia, Rubtsov, Yuri P., Ukrainskaya, Valeria M., Schulga, Alexey, Konovalova, Elena V., Volkov, Dmitry V., Yaroshevich, Igor A., Moysenovich, Anastasiia M., Belogurov, Alexey A., Zhang, Hongkai, Telegin, Georgij B., Chernov, Alexandr S., Maschan, Mikhail A., Terekhov, Stanislav S., Wu, Peng, Deyev, Sergey M., Lerner, Richard A., Gabibov, Alexander G., Altman, Sidney
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674235/
https://www.ncbi.nlm.nih.gov/pubmed/36343224
http://dx.doi.org/10.1073/pnas.2210562119
Descripción
Sumario: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.