ED SUM: The efficacy of chimeric antigen receptor (CAR)-T cells in solid tumor models is enhanced by IL23 engineering: Interleukin-23 engineering improves CAR-T cell function in solid tumors

Cytokines that stimulate T cell proliferation, such as IL15, have been explored as a means of boosting the anti-tumor activity of chimeric antigen receptor (CAR)-T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL23 is a two-subunit cytokine known to promote proliferation of memory T cells and Th17 cells. We found that, upon T cell receptor (TCR) stimulation, T cells upregulate the IL23 receptor and the IL23α p19, but not the p40, subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells), and obtained a selective proliferative activity in activated T cells via autocrine IL23 signaling. Compared to CAR-T cells, p40-Td CAR-T cells showed improved anti-tumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR-T cells showed superior efficacy compared with CAR-T cells and attenuated side effects compared with CAR-T cells expressing IL18 or IL15.