Polymeric Nanoparticle Gene Delivery to Reprogram the Tumor Immune Microenvironment in Ovarian Cancer for an Anti-Tumor Response.

Abstract

The tumor immune microenvironment (TIME) in ovarian cancer is highly immunosuppressive, and existing immunotherapies are not effective in 85-90% of patients. To address this, we fabricated nanoparticles (NPs) composed of biodegradable poly(β-amino ester) (PBAE) complexed with plasmids encoding 4-1BB ligand and interleukin-12, for delivery into ovarian cancer cells. Collectively with the intrinsic major histocompatibility complex (MHC):antigen signals in tumor cells, these NPs generate tumor-associated antigen-presenting cells (tAPCs), leading to a T-cell-mediated anti-tumor response in an antigen-agnostic manner. Ovarian cancer-bearing mice treated with tAPC NPs + anti-PD1 result in over 13% of long-term survivors and a significantly longer median survival compared to the control. In the spleen, we observe a significant (over half) reduction in FOXP3+ Tregs and over a 4X increase in the percentage of double-positive CD4+ CD8+ T cells in the tAPC NPs + anti-PD1 group compared to the control group. Depletion of T cells eliminates the therapeutic efficacy of tAPC NPs, suggesting that the anti-tumor response generated by tAPC NPs is T-cell-dependent. This work demonstrates the ability of the tAPC NP platform to be used in combination with checkpoint inhibitors to reduce immunosuppressive TIME and represents an effective, personalized yet off-the-shelf immunotherapy for ovarian cancer. STATEMENT OF SIGNIFICANCE: This study reports the development and administration of non-viral nanoparticle DNA delivery via the intraperitoneal route, aiming to overcome the immunosuppression in ovarian cancer that prevents effective activation of the large number of T cells that are normally found in the tumor microenvironment. By supplying co-stimulation and immunostimulatory cytokines directly to tumor cells, our polymeric nanoparticles reprogram tumor cells to act like antigen-presenting cells, allowing them to directly activate T cells in an antigen-agnostic manner for enhanced T-cell activation.