TY - JOUR
T1 - Switchable targeting of solid tumors by BsCAR T cells
AU - Stepanov, Alexey V.
AU - Kalinin, Roman S.
AU - Shipunova, Victoria O.
AU - Zhang, Ding
AU - Xie, Jia
AU - Rubtsov, Yuri P.
AU - Ukrainskaya, Valeria M.
AU - Schulga, Alexey
AU - Konovalova, Elena V.
AU - Volkov, Dmitry V.
AU - Yaroshevich, Igor A.
AU - Moysenovich, Anastasiia M.
AU - Belogurov, Alexey A.
AU - Zhang, Hongkai
AU - Telegin, Georgij B.
AU - Chernov, Alexandr S.
AU - Maschan, Mikhail A.
AU - Terekhov, Stanislav S.
AU - Wu, Peng
AU - Deyev, Sergey M.
AU - Lerner, Richard A.
AU - Gabibov, Alexander G.
AU - Altman, Sidney
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported in part by a grant from the JPB Foundation. S.M.D. was personally supported by grant MHSE RF no. 075152020773.
Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.
PY - 2022/11/15
Y1 - 2022/11/15
N2 - 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.
AB - 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.
KW - CAR T cells
KW - DARPins
KW - barnase–barstar interaction
KW - solid tumors
KW - switchable adoptive immunotherapy (SAI)
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U2 - 10.1073/pnas.2210562119
DO - 10.1073/pnas.2210562119
M3 - Article
C2 - 36343224
AN - SCOPUS:85141440080
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 46
M1 - e2210562119
ER -