Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells

Highlights•A chimeric cytokine receptor G6/7R captures IL-6 via extracellular IL-6 receptors•G6/7R CAR-T cells show constitutively active IL-7 signaling•G6/7R promotes CAR-T cell proliferation and effector functions•G6/7R enhances antitumor efficacy of CAR-T cells in vivoSummaryThe efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.