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

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.