Cited by 335CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting

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Srivastava, Shivani, Salter, Alexander I., Liggitt, Denny, Yechan-Gunja, Sushma, Sarvothama, Megha, Cooper, Kirsten, Smythe, Kimberly S., Dudakov, Jarrod A. +3 more·2019·Cancer Cell

Abstract

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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Crossref · 10.1016/j.ccell.2019.02.003

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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
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2019-03
Volume
35
Issue
3
Pages
489-503.e8
ISSN
1535-6108 (ISSN-L)
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
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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