Background: Ovarian cancer (OC) is immunogenic and higher lymphocytic infiltration is associated with better outcomes. Higher CD4 and CD8 T cell infiltration into OC is associated with improved survival. Other specific lymphocytes also block tumor growth including NK cells and B cells. Despite the presence of anti-tumor immune effectors, however, OCs overcome the immunologic onslaught by immune suppression strategies involving infiltration by a variety of lymphoid or myeloid derived suppressor or regulatory cells. Cells constituting this immune suppressive environment include Tregs, dendritic cells, myeloid-derived suppressor cells, neutrophils, and M2 macrophages. Tumor cells express molecules that directly block immune responses, including PD-L1, MUC16, and IL-10. Immune evasion mechanisms available to the growing tumor are abundant, and OC takes advantage of these pathways to protect against the lymphocytic adaptive and innate cytotoxic immune responses. Importantly, immune suppression in the tumor microenvironment is dynamic and adaptable to local changes. When confronted with increasing antitumor immune responses, such as those induced with immunotherapies, OCs are easily positioned to defend themselves. PD-1 and its ligands, PD-L1 and PD-L2, constitute an important regulatory (i.e., checkpoint) network that impairs effective T, B, and myeloid cell responses in the initiation and effector phases of the immune response. PD-1 is an Ig superfamily member related to CD28 and CTLA-4 and it is expressed on various cells of the adaptive and innate immune system, whereas the expression of PD-L1 is generally limited to non-hematopoietic cells. Engagement of PD-1 expressed on activated T cells by PD-L1 present on cells in the microenvironment (e.g., tumor) delivers potent inhibitory signals to T cells. The PD-1/PD-L1 axis is exploited by OC to evade immune responses. Along with CTLA-4/CD28 pathway, the PD-1/PD-L1 pathway has been the focus of several recent monoclonal antibody-based therapeutic 'checkpoint blockade' strategies that have demonstrated considerable promise in a variety of malignancies. Compared to chemotherapies, objective response rates are impressive (~30%-50%). Although trial results of PD-1/PD-L1 blockade have yet to be reported in human OC, we have recently shown in murine models that PD-1 blockade can suppress and regress tumors in the peritoneal cavity similar to the encouraging finding observed in non-small cell lung cancer and melanoma. Hypothesis: Tumor regressions in response to PD-1/PDL1 blockade constitute a minor fraction of the objective responses, suggesting that there are biologic subsets of tumors that are more amendable to checkpoint blockade or, alternatively, tumors rapidly upregulate compensatory immune suppression mechanisms, following exposure to checkpoint blockade, that prevent their destruction. This latter hypothesis is the underlying concept developed in the present application, specifically focusing on PD-1/PD-L1 blockade. An early understanding, using biologically relevant models of peritoneal metastasis and immune escape, will inform trial design and enhance implementation of combinatorial approach leading to more complete regressions and durable remissions. Specific Aims and Study Design: Preliminary studies in mouse models of OC provide evidence that alternate immune suppressive pathways are activated during checkpoint blockade with anti-PD-1 including (1) increased levels of regulatory cytokines such as IL-10, (2) upregulation of PD-L1 on myeloid cells, and (3) increased infiltration of MDSCs. Based on these observations as well as published findings that the efficacy of checkpoint blockade is limited, the following three aims are proposed in the present application to further support the overall hypothesis, thereby generating data to a support larger project of novel immune based approaches for OC. Aim 1: To identify cellular and molecular mediators of resistance to checkpoint blockade. The hypothesis to be tested is that single agent checkpoint blockade will result in upregulation of compensatory suppressive mechanisms that will prevail ultimately leading to treatment failure. Murine models of OC will be used using a murine equivalent of the human antibodies available to patients. Aim 2: To determine if co-blockade of IL-10 synergizes with anti-PD-1 to unmask T cell immunity leading to tumor rejection and improved survival. Preliminary findings show that tumors and peripheral blood become saturated with IL-10 following PD-1 blockade. It is hypothesized that co-blockade of IL-10 and/or the IL-10 receptor during treatment with anti-PD-L1 or anti-PD-1 will induce infiltration of memory CD8 and CD4 T cells leading to synergistic tumor rejection. Aim 3: To determine if pre-immunization with antigen-specific vaccines augment anti-PD-1 efficacy. A leading thought is that PD-1/PD-L1-based therapies primarily block regulatory loops in the tumor microenvironment leading to clonal expansion of anti-tumor T cells. The process of tumor eradication is slower for checkpoint blockade than chemotherapeutics. This suggests that T cell immunity activated in response to checkpoint blockade is not preformed but rather requires clonal expansion, which takes weeks to achieve, allowing sufficient time to evade and suppress the immune response. We propose the pre-immunization with multi-antigen vaccines targeting both epithelial tumor cells as well as OC stem cells will augment antigen-specific T cells to threshold levels enabling rapid deployment of tumor rejecting immunity. We will identify tumor rejection antigens that specifically target OC stem cells and which partner effectively with PD-1 blockade therapy. Innovation: There is an urgency to move away from standard toxic chemotherapies for the treatment OC, which are not effective. The innovative features include (1) understanding mechanisms used to evade checkpoint blockade in the peritoneal cavity, (2) identifying and developing novel combinatorial approaches that are not currently be tested, and (3) developing panels of overexpressed antigens that work with PD-1 blockade to maximize tumor rejection. Impact: The power of the immune system is clear and checkpoint blockade is here to stay as an alternative therapeutic approach. Early investigations such as what are proposed in this grant will establish a critical mechanistic foundation enabling well-informed future therapeutic approaches employing combination immunotherapies. In turn, we believe that this will expedite delivery of new more effective treatments for OC. According to publically available documents between 2009 and 2013, over 2,600 members of the US military or their families have been hospitalized for OC or suspected OC. These individuals have spent over 14,000 bed days of care in military treatment facilities.
|Effective start/end date||9/1/16 → 8/31/18|
- Congressionally Directed Medical Research Programs: $391,250.00