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

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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., Pierce, Robert H., Rader, Christoph, Riddell, Stanley R.·2019·Cancer Cell

DOI 10.1016/j.ccell.2019.02.003PMC PMC6450658

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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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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: Salter, Alexander I.
Liggitt, Denny
Cooper, Kirsten
Smythe, Kimberly S.
Dudakov, Jarrod A.
Pierce, Robert H.
Rader, Christoph
Riddell, Stanley R.
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2019-03
Volume: 35
Issue: 3
Pages: 489-503.e8
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccell.2019.02.003
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
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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Logic-Gated ROR1 Chimeric Antigen Receptor Expression Rescues T Cell-Mediated Toxicity to Normal Tissues and Enables Selective Tumor Targeting

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