Interleukin-23 engineering improves CAR T cell function in solid tumors

作者：H. Du, N. Porterfield Kren, D. Michaud, XiaoYan Ma, Y. Pylayeva-Gupta, B. Savoldo, Y. Xu, S. Ahn, Yining Chen, C. Smith, Ciming Sun, B. Vincent, S. Zhang, G. Dotti, P. Shou · 发表于：UNC Libraries · 年份：2021 · DOI：10.17615/9753-m703 · 被引用次数：6 · 研究领域：CAR-T cell therapy research、Biosimilars and Bioanalytical Methods

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-23α 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.