An inverted cytokine receptor (ICR) comprised of the ecto-domain of IL-4 and the endo-domain of IL-21 (4/21 ICR) was used to modify hepatoma-targeting CAR T cells. IL-4-stimulated 4/21 ICR CAR T cells activated STAT3 and upregulated expression of IL-21 target genes RORγt and CD26, consistent with a Th17 phenotype. In vitro, 4/21 ICR CAR T cells efficiently lysed IL-4-producing tumor lines with minimal expression of exhaustion markers. In NOD mice, IL-4-expressing solid tumors were more efficiently eliminated by 4/21 CAR T cells than by control CAR T cells, suggesting enhanced potency in immunosuppressive IL-4 TME.
Contributed by Samuel Goldman
Incorporation of inverted cytokine receptor (ICR) such as interleukin (IL)-4 vs. IL-7 (4/7) ICR is one strategy to improve the antitumor activities of chimeric antigen receptor (CAR) modified T (CAR-T) cells facing immunosuppressive cytokines. Here we report a novel interleukin (IL)-4 vs. IL-21 ICR (4/21 ICR) that enhanced CAR-T cell potency in IL-4(+) tumor milieu via a different working-mechanism from 4/7 ICR. Upon IL-4 stimulation, 4/21 ICR activated the STAT3 pathway and promoted Th17-like polarization and tumor-targeted cytotoxicity in CAR-T cells in vitro. Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4(+) tumors in vivo. Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.