Abstract 4210: Gene therapy approach to suppress metastasis in a mouse melanoma model

Abstract

Abstract Immune checkpoint inhibitors (ICIs) have been demonstrated to have significant clinical benefits. Effectiveness of ICIs have been limited by both primary and acquired resistance. In addition, absence of T cell infiltration within the tumor site is one of the major obstacles limiting ICIs efficacy against solid tumors. Interleukin-12 (IL-12) is a potent immune stimulator that has been shown to stimulate growth and survival of T cells as well as NK cells. Utilizing a B16.F10 melanoma model in C57Bl/6 mice, we observed a significant reduction in T regulatory cells and myeloid derived suppressor cells while T effector cells were significantly increased within the tumor microenvironment (TME) following intratumor delivery of a plasmid encoding IL-12 using gene electrotransfer. Monotherapy with plasmid IL-12 delivered with gene electrotransfer (pIL-12 GET) resulted in prolonged disease-free survival as well as long term immune memory. To determine the robustness of this therapeutic approach and to evaluate the responsiveness in combination with anti-PD1, we used a two-tumor model consisting of a subcutaneous B16F10 tumor and B16F10 cells expressing luciferase injected via the intraperitoneal route in a C57Bl/6 mouse. Intratumor delivery of pIL-12 GET as a monotherapy resulted in reduction or elimination of the subcutaneous tumor. However, the monotherapy approach was only successful in reducing the peritoneal spread in about 50% of the mice. When pIL-12 GET was combined with anti-PD1 administered via an intraperitoneal injection not only was there an elimination of the subcutaneous tumor, but it resulted in the elimination of intraperitoneal metastatic growth. The elimination of peritoneal spread was confirmed utilizing an In Vivo Imaging System. Observations on day 60 revealed background levels of luminescence in 90% of mice treated with the combination therapy thus confirming long-term disease-free survival of these mice. This level of response was not seen in mice treated with anti-PD-1 alone or with simple injection of pIL-12. In addition, the combination therapy resulted in an enhanced memory response which protected against growth of new tumors following challenge. In addition, exposure of tumor cells to IL-12 resulted in upregulation of MHC class 1 and PDL1 expression. The results have this study suggest that the combination of pIL-12 GET combined with ICIs could be utilized as an effective combination therapy for melanoma. Citation Format: Richard Heller, Megan Scott, Cathryn Mangiamele, Jody Synowiec, Guilan Shi. Gene therapy approach to suppress metastasis in a mouse melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4210.