Camel nanobody-based B7-H3 CAR-T cells show high efficacy against large solid tumours

Dan Li, Ruixue Wang, Tianyuzhou Liang, Hua Ren, Chaelee Park, Chin-Hsien Tai, Weiming Ni, Jing Zhou, Sean Mackay, Elijah Edmondson, Javed Khan, Brad St Croix and Mitchell Ho ()
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Dan Li: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Ruixue Wang: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Tianyuzhou Liang: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Hua Ren: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Chaelee Park: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Chin-Hsien Tai: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute
Weiming Ni: IsoPlexis Corporation
Jing Zhou: IsoPlexis Corporation
Sean Mackay: IsoPlexis Corporation
Elijah Edmondson: Molecular Histopathology Laboratory, Frederick National Laboratory for Cancer Research
Javed Khan: Genetics Branch, Center for Cancer Research, National Cancer Institute
Brad St Croix: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute
Mitchell Ho: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Rational design of chimeric antigen receptor T (CAR-T) cells based on the recognition of antigenic epitopes capable of evoking the most potent CAR activation is an important objective in optimizing immune therapy. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbours two distinct epitope motifs, IgC and IgV, in its ectodomain. Here, we generate dromedary camel nanobodies targeting B7-H3 and demonstrate that CAR-T cells, based on the nanobodies recognizing the IgC but not IgV domain, had potent antitumour activity against large tumors in female mice. These CAR-T cells are characterized by highly activated T cell signaling and significant tumor infiltration. Single-cell transcriptome RNA sequencing coupled with functional T-cell proteomics analysis uncovers the top-upregulated genes that might be critical for the persistence of polyfunctional CAR-T cells in mice. Our results highlight the importance of the specific target antigen epitope in governing optimal CAR-T activity and provide a nanobody-based B7-H3 CAR-T product for use in solid tumor therapy.

Date: 2023
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DOI: 10.1038/s41467-023-41631-w

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