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Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting
Open accessAbstract
Many potential targets for CAR-T cells in solid tumors are expressed in some normal tissues, raising concern for off-tumor toxicity. Following lymphodepletion, CAR-T cells targeting the tumor-associated antigen ROR1 lysed tumors in mice but induced lethal bone marrow failure due to recognition of ROR1+ stromal cells. To improve selectivity, we engineered T cells with synthetic Notch (synNotch) receptors specific for EpCAM or B7-H3, which are expressed on ROR1+ tumor cells but not ROR1+ stromal cells. SynNotch receptors induced ROR1 CAR expression selectively within the tumor, resulting in tumor regression without toxicity when tumor cells were segregated from, but not when co-localized with, normal ROR1+ cells. This strategy, thus, permits safe targeting of tumors that are sufficiently separated from normal cells.
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“the orphan receptor ROR1 is expressed on many epithelial tumors and is also a target for CAR T cells32,43.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [32]
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Metadata
- Authors
- Srivastava, S., Salter, A. I., Liggitt, D., Yechan-Gunja, S., Sarvothama, M., Cooper, K., Smythe, K. S., Dudakov, J. A., Pierce, R. H., Rader, C., & Riddell, S. R.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Scripps Research Institute (US)
- Corresponding author
- Srivastava, Shivani
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-03
- Volume
- 35
- Issue
- 3
- Pages
- 489-503.e8
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6450658
- OpenAlex
- W2921180030
- Cited by
- 334
- References
- 38
- Citations by year
- 2026: 41 · 2025: 36 · 2024: 49 · 2023: 41 · 2022: 59 · 2021: 53 · 2020: 41 · 2019: 12
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA114536)
- Cancer Center (P30 CA015704)
- Cancer Research Institute
- FHCRC
- 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
- ROR1, chimeric antigen receptor T cells, CAR T-cell toxicity, on-target off-tumor toxicity, synthetic Notch receptor, EpCAM, B7-H3, bone marrow failure, tumor stromal cells, tumor microenvironment, selective tumor targeting, solid tumors
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Humans, Neoplasms, T-Lymphocytes, Gene Expression Regulation, Neoplastic, Immunotherapy, Adoptive, K562 Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Receptor Tyrosine Kinase-like Orphan Receptors
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