Engineering T cells to express tumoricidal MDA-7/IL-24 enhances cancer immunotherapy.

Antigen-specific immunotherapy can be limited by induced tumor immunoediting (e.g., antigen loss) or through failure to recognize antigen-negative tumor clones. Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) has profound tumor-specific cytotoxic effects in a broad spectrum of cancers. Here we report the enhanced therapeutic impact of genetically engineering mouse tumor-reactive or antigen-specific T cells to produce human MDA-7/IL-24. While mock-transduced T cells only killed antigen-expressing tumor cells, MDA-7/IL-24-producing T cells destroyed both antigen-positive and negative cancer targets. MDA-7/IL-24-expressing T cells were superior to their mock-engineered counterparts in suppressing mouse prostate cancer and melanoma growth as well as metastasis. This enhanced antitumor potency correlated with increased tumor infiltration and expansion of antigen-specific T cells as well as induction of a Th1-skewed immunostimulatory tumor environment. MDA-7/IL-24-potentiated T cell expansion was dependent on T cell-intrinsic STAT3 signaling. Lastly, MDA-7/IL-24-modified T cell therapy significantly inhibited progression of spontaneous prostate cancers in Hi-Myc transgenic mice. Taken together, arming T cells with tumoricidal and immune-potentiating MDA-7/IL-24 confers new capabilities of eradicating antigen-negative cancer cell clones and improving T cell expansion within tumors. This promising approach may be used to optimize cellular immunotherapy for treating heterogeneous solid cancers and provides a mechanism for inhibiting tumor escape.