Development of a Th17-Inducing Dendritic Cell Vaccine for Ovarian Cancer
Leaders of this research project on dendritic cell vaccines and others have shown that the ability of ovarian cancer to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs), which are CD4+ T cells that cause anergy of ovarian cancer-reactive T helper 1 (Th1) and CD8+ T cells, as well as immunosuppressive changes in macrophages and dendritic cells (DCs).
Tregs are induced not only during endogenous anti-ovarian cancer immune responses but also in the context of anti-ovarian cancer vaccines, thereby limiting vaccine efficacy. However, the presence of T helper 17 (Th17) cells promotes a proinflammatory antigen-specific immune response and is associated with reduced levels of Tregs.
This Ovarian Cancer SPORE research project team has described a novel strategy of ex vivo DC maturation that leads to a robust antigen-specific Th17 response.
In a murine model of ovarian cancer, Th17-inducing DCs stimulated anti-ovarian cancer Th17 immune responses, a dramatic reduction in Tregs, and durable ovarian cancer remissions.
In parallel studies, the team also identified a novel ovarian cancer antigen, folate receptor alpha (FRα), that is overexpressed on the vast majority of human (and mouse) ovarian cancer tumors and is associated with worse clinical outcomes.
The Ovarian Cancer SPORE investigators have identified antigenic peptides from FRα, and a clinical study testing these peptides in a therapeutic vaccine has been completed.
Building on these results, the project team proposes to:
- Determine the immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines
- Assess whether 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
In addition, investigators plan to complete a vaccine therapy clinical trial to determine whether FRα specific Th17 T cell responses can be safely generated in patients with ovarian cancer following their adjuvant chemotherapy. This trial is being performed in the setting of minimal residual disease, where immunotherapy might be most effective.
Co-leaders of this Ovarian Cancer SPORE project are:
The co-investigator on the project is Martin Cannon, Ph.D., from the University of Arkansas for Medical Sciences.