Evidence map›Paper›PMID 33910979›Full record

ArticleScience translational medicine2021

SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma.

Joseph H Choe, Payal B Watchmaker, Milos S Simic, Ryan D Gilbert, Aileen W Li, Nira A Krasnow, Kira M Downey, Wei Yu, Diego A Carrera, Anna Celli and 11 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 312 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
312citing papers in PubMed, 2 pooled it
29.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

312 citing papers in PubMed, 2 syntheses or guidelines pooled it, 471 citations in OpenAlex.

  1. Mapping the clinical landscape of multifunctional CAR T cells: Targets, trends, and synergies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026
    Pooled it
  2. Pooled it
  3. Article
  4. Article
  5. Review
  6. Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.bioRxiv : the preprint server for biology · 2026
    Article
  7. Review
  8. Review
  9. Review
  10. Review
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  12. Immunotherapy for Glioma: A compartmental framework for resistance and rational combination design.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026
    Review
  13. Review
  14. Review
  15. Article
  16. Review
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  18. Article
  19. Article
  20. Adoptive cell therapies in thoracic malignancies: a comprehensive review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Review

252 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

21 authors at 5 institutions in 2 countries.

Joseph H ChoeCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-7529-7222
Payal B WatchmakerDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0944-3890
Milos S SimicCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1167-0857
Ryan D GilbertDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
Aileen W LiCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-1056-5932
Nira A KrasnowCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Kira M DowneyDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0001-7418-2239
Wei YuCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Diego A CarreraDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
Anna CelliDepartment of Veterans' Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0002-0605-0362
Juhyun ChoCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Jessica D BrionesCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.ORCID 0000-0003-3269-0379
Jason M DueckerCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Yitzhar E GoretskyDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA.
Ruth DannenfelserDepartment of Computer Science, Princeton University, Princeton, NJ 08540, USA.ORCID 0000-0002-8766-6424
Lia CardarelliDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.ORCID 0000-0002-2516-0188
Olga TroyanskayaDepartment of Computer Science, Princeton University, Princeton, NJ 08540, USA.ORCID 0000-0002-5676-5737
Sachdev S SidhuDepartment of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.ORCID 0000-0001-7755-5918
Kole T RoybalCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu.ORCID 0000-0003-3030-7954
Hideho OkadaDepartment of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu.
Wendell A LimCell Design Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. kole.roybal@ucsf.edu hideho.okada@ucsf.edu wendell.lim@ucsf.edu.ORCID 0000-0003-4052-8056
University of California, San Francisco · USPrinceton University · USUniversity of Toronto · CAHoward Hughes Medical Institute · USSan Francisco VA Medical Center · US

Funding

Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Kate Taylor Shumate · 1999 to 2026
$209.7M
Tissue CoreP50CA097257 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Susan M Chang · 2002 to 2026
$57.4M
User-control and safetyU54CA244438 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LIM, WENDELL A · 2019 to 2022
$7.8M
Preclinical development of breakthrough immunotherapy for brain tumorsR35NS105068 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI OKADA, HIDEHO · 2018 to 2025
$6.0M
Redesigning the T cell: Using Synthetic Biology to Engineer Therapeutic CellsR01CA196277 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LIM, WENDELL A · 2014 to 2018
$3.3M
Howard Hughes Medical InstituteNCI NIH HHS P30 CA082103NCI NIH HHS P50 CA097257NCI NIH HHS R01 CA196277NCI NIH HHS U54 CA244438NINDS NIH HHS R35 NS105068
6 · The paper itself

Abstract

Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.

Indexed as

Brain NeoplasmsGlioblastomaAnimalsBrainCell Line, TumorImmunotherapy, AdoptiveMiceReceptors, Antigen, T-CellT-LymphocytesXenograft Model Antitumor AssaysReceptors, Antigen, T-Cell

Identifiers

PMID33910979
PMCPMC8362330
OpenAlexW3157520262

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.