Journal Article

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

Shou, Peishun, Chen, Yuhui, Zhang, Shuqun, Pylayeva-Gupta, Yuliya, Vincent, Benjamin, Smith, Christof, Savoldo, Barbara, Dotti, Gianpietro, Ahn, Sarah, Xu, Yang, Michaud, Daniel, Du, Hongwei, Sun, Chuang, Porterfield Kren, Nancy, Ma, Xingcong

2020

Overview

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. The efficacy of chimeric antigen receptor (CAR) T cells in solid tumor models is enhanced by interleukin-23 engineering.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554 / 631/250/251 / 631/250/251/1574 / 692/308/575 / Agriculture / Analysis / Animal models / Animals / Anticancer properties / Antigen receptors, T cell / Antigens / Antitumor activity / Autocrine signalling / Bioinformatics / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cell activation / Cell culture / Cell Hypoxia - genetics / Cell Line, Tumor / Cell Proliferation / Chimeric antigen receptors / Cytokines / Granzyme B / Humans / Immunological memory / Immunotherapy, Adoptive - methods / Influence / Interleukin 15 / Interleukin 18 / Interleukin 23 / Interleukin-12 Subunit p40 - genetics / Interleukin-12 Subunit p40 - metabolism / Interleukin-23 - genetics / Interleukin-23 - metabolism / Interleukins / Life Sciences / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Memory cells / Mice / Neoplasms - immunology / Neoplasms - therapy / PD-1 protein / Prevention / Protein engineering / Receptors / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - metabolism / Receptors, Chimeric Antigen - genetics / Receptors, Chimeric Antigen - metabolism / Receptors, Interleukin - genetics / Receptors, Interleukin - metabolism / Side effects / Signal Transduction - genetics / Signaling / Solid tumors / STAT3 Transcription Factor - metabolism / T cell receptors / T cells / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Toxicity / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation