Schoutrop E, Poiret T, El-Serafi I, et al. Tuned Activation of MSLN-CAR T Cells Induces Superior Antitumor Responses in Ovarian Cancer Models. Journal for ImmunoTherapy of Cancer. 2023; 11 (2) doi: (10.1136/jitc-2022-005691).
Research suggests that calibrating CD19 chimeric antigen receptor (CAR) T-cell activation may enhance the treatment's efficacy in solid tumors. In previous work, fine-tuning intracellular CAR T signaling through mutation of CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs) has improved anti-tumor potency and persistence in models of pancreatic cancer, mesothelioma, and melanoma. The current study, using models of ovarian cancer, employed a novel CAR construct (M1xx) targeting the glycoprotein mesothelin (MSLN) — which is overexpressed in solid tumors — and encoding for the CD28 costimulatory domain. Importantly, the construct expressed a mutated CD3ζ chain containing a lone ITAM. For comparison, investigators also evaluated two traditional second-generation MSLN-CAR T cell constructs encoding for either the CD28 co-stimulatory domain (M28z) or the 4-1BB costimulatory domain (MBBz). In NSG mice that received treatment, superior anti-tumor potency and persistence were observed with the M1xx T construct compared with the M28z and MBBz versions. M1xx CAR T cells were associated with persistent tumor regression and long-term remission in vivo. They increased survival and exhibited a less exhausted phenotype ex vivo. The findings strengthen the case for using calibration of CAR T-cell activation to bolster CAR T-cell anti-tumor functions.
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