Super2-IL-33 armored CAR T cells reshape the tumor microenvironment to universally suppress solid tumor growth

Abstract

Abstract Tumor associated immunosuppressive cells limit the efficacy of CAR T cells against solid tumors. To alter immunosuppression in the tumor microenvironment, CAR T cells were armored with an IL-2 superkine (Super2) and alarmin IL-33 and adoptively transferred into immunocompetent mice with established primary or metastatic B16F10 melanoma or intradermal MC38 colon carcinoma. We show that Super2-IL-33 CAR T cells universally promoted the control of solid tumors in mice. Analysis of tumor infiltrating lymphocytes (TILs) revealed that Super2 and IL-33 expanded CAR T cells and endogenous lymphocytes cells, resulting in an increased ratio of CD8 effector T cells to regulatory T cells. The expression of the CAR or effector molecules was dispensable for CAR T cell-induced tumor control, underscoring the contribution of endogenous immune cells in mediating therapeutic efficacy. We next evaluated the effects of Super2-IL-33 CAR T cells in bone, liver, and thymus (BLT) humanized mice to assess efficacy against human tumors in an immunocompetent model. BLT mice were intradermally inoculated with Caki1, a human renal cell carcinoma in which non-treated tumors are highly enriched for regulatory T cells. To determine the impact of Super2-IL-33 armored CAR T cells on human tumors and infiltrating immune cells, tumor growth and TILs were analyzed. Super2-IL-33 armored human CAR T cells recruit endogenous immune cells to the tumor that facilitate the suppression of tumor growth. Thus, the Super2-IL-33 cytokine combination may serve as a universal platform capable of overcoming immunosuppression to promote broad anti-tumor immunity. Supported by grants from NIH (R43-CA271880 and R01-CA254042)