A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function

Abstract

The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2. In vivo, CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity. Significance: We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models. This article is highlighted in the In This Issue feature, p. 1601

Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity

“…In repeat stimulation assays without IL-15, DNMT3A KO CAR T cells still had a proliferative advantage and produced more IL-10 in comparison to Ctrl KO CAR T cells; however, the effect was less pronounced. We and others have observed differential in vitro and in vivo requirements for exogenous cytokines of CAR T cells with second genetic modifications ( 47 , 60 ), highlighting differences between in vitro culture systems and preclinical in vivo models, which more closely mimic human tumors. Alloreactivity through endogenous TCRs is a concern when second genetic modifications are introduced into CAR T cells ( 61 ).…”

Generation of an NFκB-Driven Alpharetroviral “All-in-One” Vector Construct as a Potent Tool for CAR NK Cell Therapy

“…Our group recently showed the applicability of an "all-in-one" lentiviral vector system designed to engineer primary human T cells to target GD2 + GBM (15). In line with this, other recent studies took advantage of the strategy to co-deliver an additional cytokine and showed the potential of the armored CARs (14,55). Although the feasibility, efficacy, and selectivity to induce NFAT-driven cytokine secretion in a CARdependent fashion was successfully demonstrated (15), we encountered some challenges and problems when applying the system to NK cells.…”

Engineered Cytokine Signaling to Improve CAR T Cell Effector Function

“…A possible limitation of transgenic IL-18 expression is the recent discovery of an IL-18 binding protein (IL-18BP), an immune checkpoint, that inhibits IL-18 signaling; however, approaches to develop IL-18BP-resistant IL-18 are actively being explored ( 170 ). Lastly, a recent study has highlighted that it is feasible to design chimeric switch receptors that activate IL-18 signaling pathways in CAR T cells ( 171 ).…”