Evidence map›Paper›PMID 33795428›Full record

ArticleScience (New York, N.Y.)2021

Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.

Evan W Weber, Kevin R Parker, Elena Sotillo, Rachel C Lynn, Hima Anbunathan, John Lattin, Zinaida Good, Julia A Belk, Bence Daniel, Dorota Klysz and 16 more

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

Article in Science (New York, N.Y.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 415 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
415citing papers in PubMed, 2 pooled it
38.3field-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

415 citing papers in PubMed, 2 syntheses or guidelines pooled it, 569 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
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  7. Beyond Oncology: Exploring the Expanding Role of CAR T Cell Therapy in Autoimmune and Infectious Diseases-A Systematic Review.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026
    Review
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355 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

26 authors at 3 institutions in 1 country.

Evan W WeberCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0001-5039-2899
Kevin R Parker *Department of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0001-5532-238X
Elena Sotillo *Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Rachel C LynnCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-0489-8634
Hima AnbunathanCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-8458-4845
John LattinCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Zinaida GoodCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0003-2343-5771
Julia A BelkDepartment of Computer Science, Stanford University, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0003-4724-6158
Bence DanielDepartment of Pathology, Stanford University, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-2410-8767
Dorota KlyszCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-6733-6110
Meena MalipatlollaCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Peng XuCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Malek BashtiCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sabine HeitzenederCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0001-8770-2192
Louai LabaniehCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0003-3998-7415
Panayiotis VandrisCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-4917-9019
Robbie G MajznerCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0001-6969-8011
Yanyan QiDepartment of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
Katalin SandorDepartment of Pathology, Stanford University, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0003-2892-4865
Ling-Chun ChenDepartment of Chemical and Systems Biology, Stanford University, CA 94305, USA.
Snehit PrabhuCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0001-8589-3087
Andrew J GentlesDepartment of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA 94305, USA.
Thomas J WandlessDepartment of Chemical and Systems Biology, Stanford University, CA 94305, USA.
Ansuman T SatpathyDepartment of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-5167-537X
Howard Y ChangDepartment of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.ORCID https://orcid.org/0000-0002-9459-4393
Crystal L MackallCenter for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. cmackall@stanford.edu.ORCID https://orcid.org/0000-0003-0359-9023
Stanford University · USParker Institute for Cancer Immunotherapy · USHoward Hughes Medical Institute · US

Funding

MOLECULAR &CELLULAR IMMUNOBIOLOGYT32AI007290 · NIAID · STANFORD UNIVERSITY · PI Sean Curtis Bendall, Olivia M Martinez · 1985 to 2026
$27.0M
Tumor microenvironment-dependent therapy resistanceP01CA217959 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI JULIE R PARK · 2017 to 2026
$20.7M
Understanding and Overcoming Resistance to Immunotherapies in Childhood CancersU54CA232568 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI MACKALL, CRYSTAL, MARIS, JOHN M · 2018 to 2022
$13.1M
4DN Interrogation of T Cell Exhaustion in CancerU01CA260852 · NCI · STANFORD UNIVERSITY · PI SATPATHY, ANSUMAN · 2020 to 2024
$2.6M
Single cell epigenomics in cancer immunity and immunotherapyK08CA230188 · NCI · STANFORD UNIVERSITY · PI SATPATHY, ANSUMAN · 2018 to 2020
$448k
NCI NIH HHS K08 CA230188NCI NIH HHS P01 CA217959NCI NIH HHS U01 CA260852NCI NIH HHS U54 CA232568NIAID NIH HHS T32 AI007290
6 · The paper itself

Abstract

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.

Indexed as

Epigenesis, GeneticImmunotherapy, AdoptiveAnimalsCell Line, TumorCytotoxicity, ImmunologicDasatinibDown-RegulationEnhancer of Zeste Homolog 2 ProteinEpigenomeFemaleHepatocyte Nuclear Factor 1-alphaHigh Mobility Group ProteinsHumansImmunologic MemoryLymphocyte ActivationLymphoid Enhancer-Binding Factor 1DasatinibEnhancer of Zeste Homolog 2 ProteinEZH2 protein, humanHepatocyte Nuclear Factor 1-alphaHigh Mobility Group ProteinsHNF1A protein, humanLEF1 protein, humanLymphoid Enhancer-Binding Factor 1Receptors, Chimeric AntigenTOX protein, human

Identifiers

PMID33795428
PMCPMC8049103
OpenAlexW3150736119

What OpenQuestion holds

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LicenceCC BY
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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.