Ovarian cancer (OC) is immunogenic, and higher natural immune responses against OC are associated with markedly better outcomes. These natural immune responses are mediated primarily by a group of immune cells in the body, called T cells. Higher numbers of naturally occurring T cells in the tumor predicts improved progression-free survival and improved overall survival. These findings provide a basis for thinking that we can apply immune-based therapies for the treatment of OC. This idea is attractive because the activation of an immune response can be highly specific for OC and may not have the untoward toxic effects ordinarily seen with chemotherapies. Indeed, several immunotherapy studies have been done, but the results have been disappointing because OC is very good at activating suppressive mechanisms that overcome the immune responses. Indeed, greater than 10 suppressor mechanisms have been identified that are at the disposal of OCs. In recent years, there has been the development of a class of therapies that target what are called checkpoints in the immune system. These checkpoints are naturally present in the immune system and have evolved to control of the magnitude of the immune response to prevent excessive damage to tissue following activation of the immune responses. OCs, and many other cancers, directly activate these checkpoint mechanisms to block immune responses. Scientists have speculated in recent years that blocking these checkpoint pathways may actually allow the further activation of the immune responses leading to regression of tumors, which could, in turn, lead to better outcome for patients, including complete cures. Indeed, in advanced metastatic melanoma, complete cures have been observed in patients thought to be on their last leg. These incredible findings have led to broad shift in industry toward the development of checkpoint blockade strategies. Every major pharmaceutical company is spending hundreds of millions of dollars on advancing these strategies.
There are two major checkpoints that are currently being targeted in clinical trials and have received marketing approvals from the US Food and Drug Administration. These are the CTLA-4/CD28 and PD-1/PD-L1 checkpoints. PD-1/PD-L1 checkpoint blockade is the newest addition to the clinic and is the primary focus of this application. Although ongoing 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. In terms of clinical responses to therapy, trial results in human OC are likely going to be very similar as to what has been reported for other solid tumors, which is typically 30%-40% and includes complete and partial tumor regressions as well as disease stabilizations. Although the power of checkpoint blockade is obvious from the dramatic regressions observed in other cancers, it is also obvious that we need to continue exploring how and why the approach works and does not work. I am committed to ending OC deaths and, despite the fact that PD-1/PD-L1 checkpoint blockade is not used clinically yet, I believe that now is the time to start developing a further understanding of the approach in OCs. Particularly, our goal is to understand how ovarian tumors evade checkpoint blockade. Our hypothesis is that OCs 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. I aim to develop an early understanding, using biologically relevant models, which will inform future clinical trial design and enhance implementation of combinatorial approaches leading to more complete regressions and durable remissions.
Preliminary studies in mouse models of OC provide evidence that alternate immune suppressive pathways are activated during checkpoint blockade with anti-PD-1. One mechanism is increased release of immune suppressive cytokines, which are small proteins that dampen immune responses. We found that treatment with anti-PD-1 monoclonal leads to increased release of interleukin-10 (IL-10) into the tumor microenvironment. IL-10 is one of the most immune suppressive cytokines known to immunologists. Other types of immune suppressive proteins also appear to be upregulated. Thus, our hypothesis is OCs can evade checkpoint blockade by upregulating compensatory mechanisms. In this pilot study, we will test this hypothesis in three specific aims. In the first aim, we will 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. In Aim 2, we will determine if co-blockade of IL-10 synergizes with anti-PD-1 to unmask T cell immunity, leading to tumor rejection and improved survival. In this aim, we will extend our preliminary data on increased IL-10 release in response to checkpoint blockade and test combination checkpoint and IL-10 blockade. If IL-10 is indeed compensatory, co-blockade should lead to enhanced survival. In Aim 3, we will determine if pre-immunization with antigen-specific vaccines augment anti-PD-1 efficacy. PD-1/PD-L1-based therapies primarily block regulatory loops in the tumor microenvironment, leading to the generation 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 expansion, which takes weeks to achieve, allowing sufficient time to evade and suppress the immune response. We propose that 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. 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. These facts demonstrate the relevance of OC to the US Military.
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