Project 1

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PROJECT SUMMARY The goal of our studies is to generate robust and long-lasting tumor-specific T cell responses for durable tumor regression in patients with chemotherapy-resistant high-grade serous ovarian cancer (HGSOC). Although immunotherapy using immune checkpoint inhibitors (ICI), adoptive T cell therapy (ACT), or oncolytic viruses (OV) have generated remarkable results in several tumor types (e.g. melanoma, NSCLC), long-term tumor control has been infrequent in patients with HGSOC. Studies by our group and others have identified key stumbling blocks underpinning the limited anti-tumor efficacy of immunotherapy in EOC. These include: (i) insufficient expansion of tumor antigen-specific T cells, (ii) recruitment of Tregs and myeloid-derived suppressor cells (MDSC) via tumor CXCL12 production, (iii) severe dysfunction of tumor-infiltrating T lymphocytes (TIL) often by PD1 upregulation, (iv) low intrinsic tumor immunogenicity partially dependent on reduced tumor mutation burden and IFNβ production, (viii) insufficient recruitment of intratumoral dendritic cell populations (DC) capable of cross-presenting tumor antigens; (ix) tumor “vascular checkpoint” characterized by disorganized and tortuous tumor vasculature lacking adequate flow dynamics to support trafficking of anti- tumor T cells. While combinatorial immunotherapy strategies have the potential to overcome these immune resistance mechanisms in the tumor microenvironment (TME), they are often associated with unacceptably high rates of toxicities in patients. Our proposal addresses these stumbling blocks using innovative, clinically- translatable strategies to reprogram the TME and to identify mechanisms that drive or hinder T cell trafficking into ovarian tumors. We previously demonstrated blockade of the CXCL12/CXCR4 axis in the ovarian TME by intraperitoneal delivery of an oncolytic vaccinia virus expressing a CXCR4 antagonist (OVV-CXCR4-A-Fc) reduced intratumoral accumulation of immunosuppressive mediators, stimulated spontaneous anti-tumor immunity to endogenous tumor antigens, and improved T cell trafficking into the TME. Based on our observations, we propose to test the hypothesis that in HGSOC patients receiving liposomal doxorubicin (DOX) for platinum resistant/refractory EOC, in vivo tumor destruction by OVV-CXCR4-A-Fc will (i) abrogate tumor immune suppression, (ii) promote trafficking and accumulation of tumor-specific T cells, and (iii) when combined with PDL1 blockade, will limit T exhaustion and provide clinical benefit in a phase I/II clinical trial. The approach is to first determine whether i.p. OVV-CXCR4-A-Fc is safe and triggers a transformation of the ovarian TME from tolerogenic to immunogenic in a first-in-human clinical trial focused on patients with platinum resistant/refractory EOC. Second, we will determine whether the combination of OVV-CXCR4-A-Fc and PDL1 inhibition is safe and can generate clinical efficacy. Third, we will test whether the combinatorial regimen generates functionally distinct CD8+ and CD4+ effector/memory cells for shared antigens and neoantigens. Finally, we plan to uncover the molecular mechanisms by which OVV-CXCR4-A-Fc overcomes the ovarian tumor “vascular checkpoint” to enhance T cell migration and trafficking.