Ma and Xu et al. found that TCR stimulation of memory-like T cells upregulated IL-23R and the IL-23α p19 subunit, but surprisingly not the IL-12β p40 subunit of IL-23. In xenograft and syngeneic cancer models, p40-transduced CAR (CAR.p40) or antigen-specific TCR T cells secreted IL-23 upon CAR or TCR stimulation, showed enhanced proliferation and persistence, upregulated STAT3-responsive genes, and conferred enhanced tumor control and survival. IL-23 produced by CAR.p40 T cells acted in an autocrine fashion, with limited effects on bystander cells. CAR.p40 cells had better efficacy and safety than CAR T cells expressing IL-18 or IL-15.
Contributed by Anna Scherer
ABSTRACT: Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23alpha p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor 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 in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15.