Evidence map›Paper›PMID 37989314›Full record

ArticleCell chemical biology2024

Genetic retargeting of E3 ligases to enhance CAR T cell therapy.

Isabel C Lane, Gabriele Kembuan, Jeannie Carreiro, Michael C Kann, William Lin, Amanda A Bouffard, Johannes Kreuzer, Robert Morris, Emily M Schneider, Joanna Y Kim and 8 more

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

Article in Cell chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
3.2field-weighted citation impact, top 7% 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

12 citing papers in PubMed, 14 citations in OpenAlex.

  1. Article
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  5. Article
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  9. Article
  10. Degron-based bioPROTACs for controlling signaling in CAR T cells.bioRxiv : the preprint server for biology · 2024
    Article
  11. Article
  12. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 2 institutions in 1 country.

Isabel C LaneCancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Gabriele KembuanCancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Jeannie CarreiroBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Michael C KannCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
William LinCancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Amanda A BouffardCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Johannes KreuzerCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Robert MorrisCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Emily M SchneiderHarvard Medical School, Boston, MA, USA.
Joanna Y KimCancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Charles ZouBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Diego Salas-BenitoCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Jessica A GasserBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Mark B LeickCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Mikołaj SłabickiBroad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Wilhelm HaasCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Marcela V MausCancer Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Max JanCancer Center, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: mjan@mgh.harvard.edu.
Harvard University · USBroad Institute · US

Funding

Medical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7M
Reprogramming the chimeric antigen receptor T cell epigenome to augment anti-tumor activityK08CA255932 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAN, MAX · 2021 to 2025
$951k
NCI NIH HHS K08 CA255932NIGMS NIH HHS T32 GM144273
6 · The paper itself

Abstract

Chimeric antigen receptor (CAR) T cell therapies are medical breakthroughs in cancer treatment. However, treatment failure is often caused by CAR T cell dysfunction. Additional approaches are needed to overcome inhibitory signals that limit anti-tumor potency. Here, we developed bifunctional fusion "degrader" proteins that bridge one or more target proteins and an E3 ligase complex to enforce target ubiquitination and degradation. Conditional degradation strategies were developed using inducible degrader transgene expression or small molecule-dependent E3 recruitment. We further engineered degraders to block SMAD-dependent TGFβ signaling using a domain from the SARA protein to target both SMAD2 and SMAD3. SMAD degrader CAR T cells were less susceptible to suppression by TGFβ and demonstrated enhanced anti-tumor potency in vivo. These results demonstrate a clinically suitable synthetic biology platform to reprogram E3 ligase target specificity for conditional, multi-specific endogenous protein degradation, with promising applications including enhancing the potency of CAR T cell therapy.

Indexed as

NeoplasmsUbiquitin-Protein LigasesHumansImmunotherapy, AdoptiveTransforming Growth Factor betaUbiquitinationTransforming Growth Factor betaUbiquitin-Protein Ligasescancer immunotherapyCAR T cellcellular immunotherapysynthetic biologytargeted protein degradationubiquitin

Identifiers

PMID37989314
PMCPMC10922718
OpenAlexW4388824769

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.