American Association for Cancer Research
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Supplementary Fig. S9 from Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy

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posted on 2024-04-15, 07:21 authored by Rosa Nguyen, Ekaterina Doubrovina, Charlotte M. Mousset, Benjamin Y. Jin, Reona Okada, Xiyuan Zhang, Arina Clavel, Jeyshka M. Reyes-Gonzalez, Vadim Dyomin, Louis Diaz, Ling Zhang, Shahroze Abbas, Ming Sun, Chao-Ming Hsieh, Mitchell Ho, Jack F. Shern, James L. Gulley, Christian S. Hinrichs

Violin plots showing common marker expression by cluster.

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National Cancer Institute (NCI)

United States Department of Health and Human Services

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St. Baldrick's Foundation (SBF)

Rutgers Cancer Institute of New Jersey (CINJ)

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ARTICLE ABSTRACT

Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL15 and IL21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T cells and other lymphocytes, to enhance the efficacy of adoptive T cells. We designed vectors that induce the constitutive expression of either membrane-tethered IL15, IL21, or IL15/IL21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T cells for human administration. We found that self-delivery of these cytokines by CAR or TCR T cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T cells. Across different preclinical murine solid tumor models, we observed enhanced regression with each individual cytokine but the greatest antitumor efficacy when T cells were armored with both. The coexpression of membrane-tethered IL15 and IL21 represents a technology to enhance the resilience and function of engineered T cells against solid tumors and could be applicable to multiple therapy platforms and diseases.See related commentary by Ruffin et al., p. 1431

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