? Project 8 The host immune response to ovarian cancer (OvCa) has been repeatedly demonstrated and has a dramatic association with survival; however, for the majority of patients, immune control of OvCa is temporary, and the tumor cells persist, grow, and ultimately lead to patient death. We and others have shown that this ability of OvCa to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs) and suppressive myeloid cells. Both Tregs and suppressive myeloid cells cause anergy of OvCa-reactive T helper 1 (Th1) and CD8 T cells. Tregs are induced not only during endogenous anti-OvCa immune responses, but also in the context of anti-OvCa immunotherapies, thereby limiting efficacy. Multiple groups have made efforts to target suppressor cells in OvCa using chemotherapy agents and toxins, but the effects of these agents are transient and can also deplete beneficial cell types. In contrast, T helper 17 (Th17) cells have been demonstrated to downregulate these suppressor cells while simultaneously promoting a proinflammatory antigen-specific immune response. We have recently described a novel strategy of ex vivo DC maturation that leads to a robust antigen-specific Th17 response. In a model of OvCa, mice treated with Th17-inducing DCs demonstrated robust anti-OvCa Th17 immune responses, a dramatic reduction in Tregs, and durable OvCa remissions. In addition to our studies demonstrating the promise of generating Th17 immune responses using DCs matured ex vivo, we have also identified a novel OvCa antigen, the folate receptor alpha (FR?). This protein is overexpressed on the vast majority of human (and mouse) OvCa tumors and is linked to worse clinical outcomes. We have, therefore, identified antigenic peptides from FR? and completed a clinical study testing these peptides in a therapeutic vaccine. Building on these results, we propose to 1) identify the immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines, 2) determine whether the induction of Th17 immune responses targeting ovarian cancer antigens will overcome local tumor immune suppression by inhibiting Treg generation and modulating infiltrating myeloid cell function, and 3) perform a phase 1 clinical trial to determine whether FR?-specific Th17 T cell responses can be safely generated in OvCa patients following conventional therapy. Collectively, these aims will help elucidate the mechanisms by which Th17-inducing DC vaccination suppresses tumor growth, and will provide an assessment of safety and immunogenicity of this strategy for human OvCa patients, fostering the continuation of a Mayo SPORE program of innovative immune-based approaches for preventing disease recurrence in OvCa.
We propose to study the mechanistic basis for the dramatic preclinical efficacy demonstrated by maturation of Th17-inducing dendritic cells (DCs) for an ovarian cancer (OvCa) vaccine ex vivo, as well as conduct a pilot clinical trial using this approach in patients with advanced stage OvCa in remission after initial therapy. These studies will improve our understanding of the role of DC-induced Th17 cells in controlling OvCa, and will allow assessment of the safety and immune effects of this approach in OvCa patients.
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