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Nat. Commun., 18 November 2024 | https://doi.org/10.1038/s41467-024-53996-7
Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters
Hyung Bae Park1,2,3, Ki Hyun Kim1,3, Ju Hwan Kim4, Sang Il Kim1,3, Yu Mi Oh1, Miseung Kang1,2, Seoho Lee1,2, Siwon Hwang1,2, Hyeonmin Lee1,3, TaeJin Lee4,5, Seungbin Park5, Ji Eun Lee1,3, Ga Ram Jeong1,6, Dong Hyun Lee7, Hyewon Youn3,8, Eun Young Choi2,9, Woo Chan Son10, Sang J. Chung5,11, Junho Chung1,2,3,11 & Kyungho Choi1,2,3,11
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
4AbTis Co. Ltd., Suwon, Gyeonggi-do, Republic of Korea.
5Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
6Ticaros Inc., Seoul, Republic of Korea.
7Department of Medical Science, AMIST, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
8Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea.
9Institute of Human Environment Interface Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
10Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
11These authors jointly supervised this work: Sang J. Chung, Junho Chung, Kyungho Choi.
Corresponding authors
Correspondence to Sang J. Chung, Junho Chung or Kyungho Choi.
1Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
4AbTis Co. Ltd., Suwon, Gyeonggi-do, Republic of Korea.
5Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
6Ticaros Inc., Seoul, Republic of Korea.
7Department of Medical Science, AMIST, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
8Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea.
9Institute of Human Environment Interface Biology, Seoul National University College of Medicine, Seoul, Republic of Korea.
10Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
11These authors jointly supervised this work: Sang J. Chung, Junho Chung, Kyungho Choi.
Corresponding authors
Correspondence to Sang J. Chung, Junho Chung or Kyungho Choi.
Abstract
Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-19)
- 국내 연구진
- 의약학 > 면역의학
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