Abstract 486: Intratumor gene therapy designed to induce both local and systemic tumor directed immune responses

Abstract Immune checkpoint inhibitors (ICIs) have provided a major breakthrough for the treatment of multiple cancer types. While there have been significant clinical benefits, the therapy has been limited by both primary and acquired resistance. The immune state of the tumor microenvironment (TME) can play a significant role in ICI effectiveness. Modifying the TME to increase lymphocytic infiltrate and/or increasing expression of checkpoints can improve ICI efficacy. 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) 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 systemic immune response when combined with ICIs. The key to make this an effective therapy is to deliver these agents in a manner that has minimal adverse and off target effects while still inducing the desired response. We have designed a novel approach to efficiently deliver multiple plasmids directly to solid tumors. The rationale was based on the premise that by performing intratumor delivery, stimulation would be directed against the specific antigens within the TME to produce an effective local response while stimulating a systemic response, resulting in an abscopal effect. This delivery utilizes a next generation electrotransfer device that enables the use of significantly reduced voltages and includes a means to monitor when successful delivery has occurred. We tested this concept in the B16.F10 mouse melanoma model. Intratumor delivery of pIL-12 resulted in effective control of the treated tumor in over 90% of the mice and generated resistance to challenge. To fully test this approach, we next evaluated a combination therapy delivering both pIL-12 combined with a plasmid encoding a PD1 peptide, an alternative form of checkpoint inhibitor. The therapy was tested in a multi-tumor model which included a subcutaneous tumor and intraperitoneal injection of tumor cells. The plasmids were delivered to the subcutaneous tumor; tumors generated by intraperitoneal injection were untreated. Peritoneal tumor growth was not affected by single plasmid delivery or when both plasmids were delivered using other delivery approaches or older electrotransfer technology. However, this new therapy induced complete regression of the subcutaneous tumor and blockage of peritoneal tumor growth as assessed via in vivo imaging. Work is ongoing to translate this approach to clinical evaluation. Citation Format: Richard Heller, Loree C. Heller, Jody Synowiec, Julie Singh, Alex Otten, Mark J. Jaroszeski. Intratumor gene therapy designed to induce both local and systemic tumor directed immune responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 486.