Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy.

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.