U01 Proposal Transfer - 2021

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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 epithelial ovarian cancer (EOC). Although immunotherapy using immune checkpoint blockade, adoptive T cell therapy, or oncolytic viruses has generated remarkable results in several other tumor types, long-term tumor control has been infrequent in EOC patients. Studies by our group have identified key stumbling blocks underpinning the limited efficacy of immunotherapy in EOC, which include: (i) tumor-derived CXCL12 production that recruits intra-tumoral T regulatory cells and suppressive myeloid cells, (ii) expression of multiple co-inhibitory receptors on tumor infiltrating T lymphocytes (TIL), (iii) compensatory upregulation of immune checkpoints upon blockade of one pathway, (iv) low intrinsic tumor immunogenicity partially dependent on reduced IFNβ production, (v) inability of TIL to resist immune suppression mediated by inhibitory cytokines such as TGFβ, and (vi) adaptive upregulation of immune inhibitory checkpoints. While combinatorial immunotherapy strategies have the potential to overcome these intrinsic and adaptive immune resistance mechanisms, they are often associated with unacceptably high rates of toxicities in patients. Our proposal addresses these stumbling blocks using innovative, clinically translatable, state-of-the-art strategies to concomitantly reprogram the tumor microenvironment (TME) and T cells, while minimizing the potential for high rates of systemic toxicities. We have previously demonstrated that an oncolytic vaccinia virus armed with a CXCR4 antagonist (OV-CXCR4-Fc) results in direct tumor oncolysis but is incapable of preventing tumor recurrence due to upregulation of multiple immune checkpoint receptors and insufficient persistence of T cells in the TME due to increasing levels of immunosuppressive TGFb. To overcome these limitations, we propose to test the efficacy of a multifaceted oncolytic virus incorporating the CXCR4 antagonist and multiple checkpoint inhibitors, followed by adoptive transfer of tumor antigen-specific T cells engineered to resist TGFβ. We hypothesize that in vivo tumor destruction by the multipotent oncolytic virus will limit dampening of the immune response in the TME and thus further promote the infiltration and sustained anti-tumor function of the transferred T cells engineered to resist TGFβ. To test this hypothesis, we propose three specific aims: Aim 1. To select the optimal combination of oncolytic vaccinia virus-delivered immune checkpoint inhibitors that would effectively augment the efficacy of OV-CXCR4-Fc. Aim 2. Determine the therapeutic synergy of OV-CXCR4-Fc-MICB with adoptively transferred T cells that are rendered insensitive to TGFβ. Aim 3. To manufacture and certify a Master Viral Bank (MVB) and Final Product (FP) of recombinant oncolytic vaccinia virus selected in Aims 1 and 2 for IND qualification.