Research ArticleCAR-T CELLS

Engineering γδT cells limits tonic signaling associated with chimeric antigen receptors

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Science Signaling  10 Sep 2019:
Vol. 12, Issue 598, eaax1872
DOI: 10.1126/scisignal.aax1872

Taming tonic signaling

Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) is an effective therapy for select lymphomas. The potency of this therapy can be limited by antigen-independent (tonic) signaling, which promotes progressive CAR-T cell inactivation. Fisher et al. used mass cytometry to analyze CAR-T cells and found that the process of increasing αβ T cell numbers during CAR-T cell production (expansion) was sufficient to increase tonic signaling in αβ T cells. In contrast, expansion of γδT cells did not alter their basal activity. When these cells were engineered to express a chimeric costimulatory receptor, they specifically recognized transformed, but not healthy, myeloid cell targets. These data demonstrate a strategy for engineering specific antitumor responses free of the complications associated with tonic signaling.

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