Abstract 7240: Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses

Abstract Immune checkpoint inhibitors (ICIs) have significant clinical benefits, but are limited by both primary and acquired resistance. The absence of T cells within the tumor microenvironment (TME) is a significant hurdle, reducing the efficacy of ICIs against solid tumors. Multiple studies have been initiated to modify the TME to enhance the effectiveness of ICIs. We previously demonstrated that the intratumor delivery of a plasmid encoding interleukin-12 (pIL-12) using gene electrotransfer (GET) resulted in a significant increase in T effector cells and a reduction in T regulatory cells and myeloid derived suppressor cells within the TME, inducing a robust immune response. Combining pIL-12 GET with ICIs resulted in local and systemic responses in both preclinical and clinical studies. While encouraging results were obtained, improvements were possible. For example, the established GET technology requires high applied voltage for plasmid delivery. In addition, satisfactory delivery cannot be immediately detected. Our current research has focused on developing the next generation GET technology to overcome these issues. This new system includes a pulse generator, a heat source and a tissue impedance measuring device. An array that incorporates independently addressable electrodes was also developed. A moderate elevation of the tissue temperature coupled with the electrode array enabled a 75% reduction in the applied voltage. We tested the approach in the B16.F10 mouse melanoma model. Delivery of pIL-12 with the new system resulted in 100% long-term complete regression and 100% protection from challenge. In addition, monitoring impedance within each independent section of the electrode array revealed different pulse numbers were needed to achieve delivery in each section. We next evaluated a combination therapy, pIL-12 plasmid combined with a plasmid encoding a PD1 peptide, delivered with the next-gen device. In a multi-tumor model, the plasmids were delivered to the subcutaneous tumor; tumors generated with an intraperitoneal injection were untreated. This new therapy induced complete regression of the subcutaneous tumor and blockage of peritoneal tumor growth as assessed via in vivo imaging. Peritoneal tumor growth was not affected by single plasmid delivery or when both plasmids were delivered with the established GET technology. Work is ongoing to translate this approach to clinical evaluation. Citation Format: Richard Heller, Loree C. Heller, Guilan Shi, Jody Synowiec, Julie Singh, Alex Otten, Mark J. Jaroszeski. Intratumor delivery of plasmid DNA encoding immune stimulating agents induces both local and systemic responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7240.