Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters

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.

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Publication Details

Journal
Nature Communications
Published
2024-11-18
DOI
https://doi.org/10.1038/s41467-024-53996-7
Citations
19
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
5.37

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article

Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters

Tae Jin Lee, Sang Jeon Chung, Ju Hwan Kim, Ga Ram Jeong et al.
19 citations
Nature Communications
CAR-T cell therapy research
5.37
article

Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters

Tae Jin Lee, Sang Jeon Chung, Ju Hwan Kim, Ga Ram Jeong, Siwon Hwang, Hyung Bae Park, Junho Chung, Kyungho Choi, Woo‐Chan Son, Hyewon Youn, Min Ju Kang, Seoho Lee, Ji‐Eun Lee, Sang Il Kim, Dong Hyun Lee, Ki Hyun Kim, Eun Young Choi, Ho‐Jin Lee, Yu Mi Oh, S H Park
article en
19 citations

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.

Nature CommunicationsVol. 15(1)
Ulsan College (KR), Seoul National University (KR), Cancer Research Institute (US), Korea International Cooperation Agency (KR), Asan Medical Center (KR), Seoul National University Hospital (KR), University of Ulsan (KR), National University College (PR), Sungkyunkwan University (KR)
National Research Foundation, Seoul National University, Ministry of Trade, Industry and Energy, National Research Foundation of Korea, Korea Drug Development Fund, Ministry of Science and ICT, South Korea, College of Medicine, Seoul National University
Affordable and clean energy
Openalex Percentile: Top 3%
CAR-T cell therapy research
5.37
DOIOpen Access PDFOpenAlex
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