Published in

American Association for Cancer Research, Clinical Cancer Research, 2023

DOI: 10.1158/1078-0432.ccr-23-1872

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Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

Abstract Purpose: 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 IL-15 and IL-21, 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. Experimental Design: We designed vectors that induce the constitutive expression of either membrane-tethered IL-15, IL-21, or IL-15/IL-21. 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. Results: 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 anti-tumor efficacy when T-cells were armored with both. Conclusion: The co-expression of membrane-tethered IL-15 and IL-21 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.