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Fixing a single genetic mutation in A20 may improve CAR-T cell cancer therapy

Updated

Abstract

Essence

Base-editing one A20 missense mutation made CAR-T cells more resistant to exhaustion and more suppressive against cancer in the reported models.

Evidence

This was a preclinical immunotherapy study using genome-wide screening in repetitively stimulated human T cells, protein modeling, deep base-editing mutagenesis, immunocompetent mouse studies, tumor-infiltrating lymphocyte analyses, and engineered human CAR-T cells.

Caveat

The evidence combines cell and mouse-model systems, so the CAR-T efficacy signal is preclinical and not yet human clinical outcome evidence.

Simplified

Full Text

Full text is available at the source.

Funding

Competing interests

A. Ma is a consultant for Conveyor Therapeutics. J.E. is a compensated co-founder at Mnemo Therapeutics and Azalea therapeutics. J.E. owns stocks of Mnemo Therapeutics, Azalea Therapeutics and Cytovia Therapeutics. J.E. has received a consulting fee from Casdin Capital, Resolution Therapeutics, Azalea Therapeutics and Treefrog Therapeutics. The Eyquem lab has received research support from Cytovia Therapeutics, Mnemo Therapeutics, and Takeda Pharmaceutical Company. C.J.Y. is the founder of and holds equity in DropPrint Genomics (now ImmunAI) and Survey Genomics. He serves as a Scientific Advisory Board member for and holds equity in Related Sciences and ImmunAI, and is a consultant or has consulted for Maze Therapeutics, TReX Bio, HiBio, ImYoo, Kiragen, and Santa Ana Bio. Additionally, C.J.Y. is an Innovation Investigator at the Arc Institute. He has received research support from the Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Initiative, Chan Zuckerberg Biohub, Genentech, BioLegend, ScaleBio, and Illumina. A. Marson is a cofounder of Site Tx, Arsenal Biosciences, Spotlight Therapeutics and Survey Genomics, serves on the boards of directors at Site Tx, Spotlight Therapeutics and Survey Genomics, is a member of the scientific advisory boards of Site Tx, Arsenal Biosciences, Cellanome, Spotlight Therapeutics, Survey Genomics, NewLimit, Amgen, and Tenaya, owns stock in Arsenal Biosciences, Site Tx, Cellanome, Spotlight Therapeutics, NewLimit, Survey Genomics, Tenaya and Lightcast and has received fees from Site Tx, Arsenal Biosciences, Cellanome, Spotlight Therapeutics, NewLimit, Abbvie, Gilead, Pfizer, 23andMe, PACT Pharma, Juno Therapeutics, Tenaya, Lightcast, Trizell, Vertex, Merck, Amgen, Genentech, GLG, ClearView Healthcare, AlphaSights, Rupert Case Management, Bernstein and ALDA. A.Marson is an investor in and informal advisor to Offline Ventures and a client of EPIQ. The Marson laboratory has received research support from the Parker Institute for Cancer Immunotherapy, the Emerson Collective, Arc Institute, Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead and Anthem and reagents from Genscript and Illumina. A.A. is a co-founder of Azkarra Therapeutics, Kytarro, Ovibio Corporation, Tango Therapeutics, Tiller tx, a member of the board of Cambridge Science Corporation, Cytomx, a member of the scientific advisory board of Ambagon, Bluestar/Clearnote Health, Circle, Genentech, GLAdiator, HAP10, Earli, ORIC, Phoenix Molecular Designs, Trial Library, Yingli/280Bio and a consultant for Next RNA, Novartis, ProLynx; he holds patents on the use of PARP inhibitors held jointly with AstraZeneca from which he has benefited financially (and may do so in the future). A.B., S.B., L.R.S., J.E., J.C., B.A.M. and A. Ma are listed on patent applications related to this work.
PubMed

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