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 |
|