Abstract B050: IMNN-001, an IL-12 gene therapy, added to Neo/Adjuvant chemotherapy safely turns the tumor microenvironment cold-to-hot in newly diagnosed epithelial ovarian cancer (EOC)

Abstract Introduction: 80% of Epithelial Ovarian Cancers (EOC) are diagnosed in advanced stage (III/IV), and >60% of ovarian cancer patients die within 5 years. Neo/Adjuvant (N/ACT) peri-debulking surgery remains SoC treatment, followed by maintenance PARPi for non-progressing patients with HRD. Although immunotherapy is an attractive approach for treatment of EOC due to its highly immunosuppressive (“cold”) tumor environment (TME), the addition of immune checkpoint inhibitors to SoC has only modestly improved ORR with no survival benefit. IL-12 is a pleiotropic immuno-stimulatory cytokine with activity in both the innate and adaptive immune systems and can turn “cold” TME to “hot”. However, systemic treatment with IL-12 protein results in unacceptable toxicity in the clinic. The randomized, controlled Phase I/II OVATION-2 study has shown that IMNN-001, an IL-12 gene –based nanoparticle delivered locally (intraperitoneally), limits systemic exposure and in combination with N/ACT is safe and improves PFS and OS by 3 and 13 months respectively, as compared with the chemotherapy control arm. Herein, we characterize the immune effects of IMNN-001 on patients’ TME. Methods: Paired tumor samples obtained pre-treatment at screening biopsy and post-IMNN-001 and NACT treatment at debulking surgery from patients with High Grade Serous Ovarian Cancer (HGSC) were analyzed for immune marker expression in tumor and TME by cyclic immunofluorescence analysis (Phenocycler-fusion) for the following markers: CD8, CD11c, CD44, CD4, HLA-DR, CD45, CD45RO, Ki67, CD14, CD3e, CD20, HLA-A, CD68, CD163, CD11b, CD16, Pan CK, FOXP3, PD-L1, PD-1, IDO-1. Cells in specimens segmented by a pathologist were quantified and normalized by tissue area. Results: Of the six paired samples studied, two showed focal infiltration of predominantly CD4+ and CD8+ T cells (tertiary lymphoid nodules) and four showed diffuse immune infiltration post-treatment. Overall, trends of decreases in immune suppressive cells/mm2 (M2 and g- and mMDSC) and increases in anti-tumoral M1 and myeloid DCs were identified. A favorable CD8/Treg ratio was also observed, along with a decrease in exhausted CD4+ and CD8+ cells in the TME. Further immunophenotypic analysis will be presented at the Congress. Conclusions: IMNN-001 induces T and myeloid cell-mediated anti-tumoral responses across the heterogeneous TMEs characteristic of HGSC, likely driven by the multifaceted actions of IL-12 on both innate and adaptive immune systems. The ability of IMNN-001 to generate IL-12, IFN-γ, and TNF-α locally and the induction of a “hot” TME, collectively support the safety and efficacy observed in the OVATION-2 trial. A Phase III trial (OVATION-3, NCT06915025) is currently enrolling. Citation Format: Kursheed Anwer, Subeena Sood, Lauren Musso, Danielle Blume, Jeff Sparks, Ana Limon, Stacy Lindborg, Douglas V. Faller. IMNN-001, an IL-12 gene therapy, added to Neo/Adjuvant chemotherapy safely turns the tumor microenvironment cold-to-hot in newly diagnosed epithelial ovarian cancer (EOC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B050.