Intratumor delivery of a novel plasmid combination induces high levels of metastatic melanoma regression

Direct intratumoral administration of immune-stimulating agents can generate systemic immunity following a tumor-localized immune response. Interleukin 12 (IL-12) activates T cells and reverses immunosuppression, generating a localized patient-antigen-specific immune response. Changes in the tumor microenvironment in response to this cytokine facilitate the function of checkpoint inhibitors. In this study, a plasmid (p)-based approach was used to generate intratumor expression of IL-12 protein and of a polypeptide designed to inhibit PD-1/PD-L1 binding, potentially to function as a checkpoint inhibitor. An updated technology, heat-and-impedance gene electrotransfer (HIGET), was used for tumor transfection to increase the reproducibility of protein expression. Efficacy was evaluated in a difficult mouse model combining subcutaneous and intraperitoneal melanomas. While each monotherapy, pIL-12 HIGET or pPD1ex HIGET, significantly increased mouse survival, the combination therapy produced significantly longer survival times than either monotherapy alone.