Research ArticleCAR T CELLS

Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function

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Science Signaling  21 Aug 2018:
Vol. 11, Issue 544, eaat6753
DOI: 10.1126/scisignal.aat6753

Strength limits potency

T cells engineered to express chimeric antigen receptors (CARs) may represent a curative treatment for B cell malignancies. To understand how to optimize these therapies, Salter et al. used phosphoproteomics to compare the activities of CARs encoding CD28 or 4-1BB costimulatory domains in primary human T cells. Although CARs with CD28 domains provoked more robust signaling than did CARs with 4-1BB domains (due to constitutive Lck association), both CARs activated overlapping T cell signaling pathways. However, CARs that initiated stronger signals also exhibited increased T cell dysfunction, which reduced their potency in a mouse model of lymphoma. These data indicate that the CAR costimulatory domain does not predict the signaling pathways activated in CAR T cells but instead suggest that reducing the strength of signaling may counterintuitively enhance CAR T cell therapeutic efficacy.

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