RRC ID 82383
Author Yoshikawa T, Ito Y, Wu Z, Kasuya H, Nakashima T, Okamoto S, Amaishi Y, Zhang H, Li Y, Matsukawa T, Inoue S, Kagoya Y.
Title Development of a chimeric cytokine receptor that captures IL-6 and enhances the antitumor response of CAR-T cells.
Journal Cell Rep Med
Abstract The efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy is suboptimal in most cancers, necessitating further improvement in their therapeutic actions. However, enhancing antitumor T cell response inevitably confers an increased risk of cytokine release syndrome associated with monocyte-derived interleukin-6 (IL-6). Thus, an approach to simultaneously enhance therapeutic efficacy and safety is warranted. Here, we develop a chimeric cytokine receptor composed of the extracellular domains of GP130 and IL6RA linked to the transmembrane and cytoplasmic domain of IL-7R mutant that constitutively activates the JAK-STAT pathway (G6/7R or G6/7R-M452L). CAR-T cells with G6/7R efficiently absorb and degrade monocyte-derived IL-6 in vitro. The G6/7R-expressing CAR-T cells show superior expansion and persistence in vivo, resulting in durable antitumor response in both liquid and solid tumor mouse models. Our strategy can be widely applicable to CAR-T cell therapy to enhance its efficacy and safety, irrespective of the target antigen.
Volume 5(5)
Pages 101526
Published 2024-5-21
DOI 10.1016/j.xcrm.2024.101526
PII S2666-3791(24)00195-2
PMID 38670095
PMC PMC11148643
MeSH Animals Cell Line, Tumor Cytokine Receptor gp130 / metabolism Humans Immunotherapy, Adoptive* / methods Interleukin-6* / immunology Interleukin-6* / metabolism Mice Neoplasms / immunology Neoplasms / therapy Receptors, Chimeric Antigen* / immunology Receptors, Chimeric Antigen* / metabolism Receptors, Cytokine / genetics Receptors, Cytokine / metabolism Receptors, Interleukin-6 / metabolism Receptors, Interleukin-7 / metabolism T-Lymphocytes* / immunology T-Lymphocytes* / metabolism Xenograft Model Antitumor Assays
Resource
Cord blood stem cells for research