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Cited by 23CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Synthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies

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Dobrin, Anton, Lindenbergh, Pieter L., Shi, Yuzhe, Perica, Karlo, Xie, Hongyao, Jain, Nayan, Chow, Andrew, Wolchok, Jedd D. +3 more·2024·Nature Cancer
DOI 10.1038/s43018-024-00744-xPMC PMC11921049
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Abstract

Chimeric antigen receptor T cells have dramatically improved the treatment of hematologic malignancies. T cell antigen receptor (TCR)-based cell therapies are yet to achieve comparable outcomes. Importantly, chimeric antigen receptors not only target selected antigens but also reprogram T cell functions through the co-stimulatory pathways that they engage upon antigen recognition. We show here that a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, termed 80BB, acts as both a ligand and a receptor to engage the CD28 and 4-1BB pathways, thereby increasing the antitumor potency of human leukocyte antigen-independent TCR (HIT) receptor- or TCR-engineered T cells and tumor-infiltrating lymphocytes. Furthermore, 80BB serves as a switch receptor that provides agonistic 4-1BB co-stimulation upon its ligation by the inhibitory CTLA4 molecule. By combining multiple co-stimulatory features in a single antigen-agnostic synthetic receptor, 80BB is a promising tool to sustain CD3-dependent T cell responses in a wide range of targeted immunotherapies. Dobrin et al. develop a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, which engages the CD28 and 4-1BB pathways and increases the antitumor potency of HLA-independent (HIT) and TCR-engineered T cells.

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Authors
Dobrin, A., Lindenbergh, P. L., Shi, Y., Perica, K., Xie, H., Jain, N., Chow, A., Wolchok, J. D., Merghoub, T., Sadelain, M., & Hamieh, M.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Weill Cornell Medicine (US)
Corresponding author
Sadelain, Michel
ORCID
Venue
Nature Cancer
Publisher
Springer Science and Business Media LLC
Published
2024-03-19
Volume
5
Issue
5
Pages
760-773
ISSN
2662-1347 (ISSN-L)
DOI
10.1038/s43018-024-00744-x
PMC
PMC11921049
OpenAlex
W4392955797
Cited by
23
References
7
Citations by year
2026: 10 · 2025: 8 · 2024: 5
FWCI
3.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cancer (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30 CA08748)
  • Lake Road Foundation Lymphoma and Leukemia Society The Pasteur-Weizmann/Servier award The Leopold Griffuel award
  • Gouvernement du Canada | Canadian Institutes of Health Research (CIHR-IRSC:0207000741)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
CD80, 4-1BB, CD28 costimulation, CTLA-4, T cell costimulation, TCR-engineered T cells, tumor-infiltrating lymphocytes, antitumor T-cell responses, hematologic malignancies
MeSH terms
Receptors, Chimeric Antigen, Animals, Humans, Lymphocyte Activation, Receptors, Antigen, T-Cell, T-Lymphocytes, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, CD28 Antigens, B7-1 Antigen, Mice, Tumor Necrosis Factor Receptor Superfamily, Member 9, CTLA-4 Antigen, Cell- and Tissue-Based Therapy

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