A phase I/II study of combined therapy with Th17-inducing dendritic cells and pembrolizumab in patients with recurrent epithelial ovarian cancer - ABSTRACT Ovarian cancer (OC) causes ~14,000 deaths each year in the USA. While there have been advances in treatment, progression is common and cure rates are low. In recent years, several trials have been done testing immune checkpoint blockade (ICB), either alone or in combination with other agents, largely in the setting of recurrent disease. Overall response rates have been unimpressive. Biomarkers of response to ICB therapy, such as mutational burden, neoantigen load, PD-L1 expression, and baseline T cell infiltration, are associated with response to ICB therapy in many cancers and suggest that ICB therapy requires pre-existent immunity for clinical effectiveness. Vaccines, while inefficient alone at shrinking tumor, can reliably generate the necessary pre-existing immunity, including in most OC patients. In a prior NCI-funded grant (P50- CA136393), we developed a folate receptor alpha (FR) targeting Th17-inducing vaccine that is effective at generating Th17 T cell immunity in nearly all OC patients. The premise for developing the vaccine was based on extensive work showing i) a reciprocal relationship between Th17 effectors and Tregs, ii) association of increased IL-17 expression with improved overall survival, and iii) resistance of Th17 T cells to immune suppression. A phase I clinical trial was conducted in which 19 advanced OC patients, in first remission, were vaccinated. All patients demonstrated coordinated cellular and humoral immunity. Of 18 patients evaluable for efficacy, 39% (7/18) remained recurrence-free at the time of data censoring, with a median follow-up of 49.2 months, a recurrence-free survival (RFS) superior to historical controls(<15%). Parallel murine modeling demonstrated a unique mechanism in which Th17 T cell immunity coordinates otherwise inefficient Th1, Th2 and B cell immunity through myeloid recruitment and activation of antibody-dependent mechanisms in macrophages and eosinophils. We observed that Th17 DC vaccination overcomes resistance to ICB therapy by generating tumor-specific immunity, restructuring the tumor microenvironment, and preventing adaptive resistance to ICB. Thus, we hypothesize that the combination of Th17-inducing DC vaccination and ICB therapy may be an effective therapeutic approach in patients with recurrent OC. In specific Aim 1 we will conduct a phase I/II clinical trial of the novel Th17-inducing DC vaccine in combination with pembrolizumab (provided by Merck) in 32 OC patients in the setting of early disease recurrence. Primary outcome measures will be safety and the rate of objective responses. Interrogation of baseline tumor features will be done for biomarker identification. In Specific Aim 2 we will use well validated analytical tools to examine cellular and humoral immune responses in tissue and the periphery following combination treatment to identify dominant features of the immune response induced by treatment and whether they are correlate with clinical outcome assessments. Mechanisms of resistance to therapy will be identified. If positive, a new treatment ICB treatment paradigm will be established to improve the survival of women afflicted with advanced OC.
