Cheryl M. Czerlanis

Ovarian cancer is a lethal gynecologic malignancy with limited effective treatment options. It is expected that in 2026 there will be about 21,010 new cases of ovarian cancer diagnosed and about 12,450 deaths within the United States. Unfortunately, conventional therapies such as chemotherapy and radiation have limited efficacy for high-grade serous ovarian cancer (HGSOC) and also produce significant toxicity. HGSOC is characterized by an ovarian tumor microenvironment (TME) consisting of immune inhibitory T regulatory cells and inhibitory tumor-associated macrophages, including myeloid-derived suppressor cells (MDSCs) and M2 cells, which confer immune suppression. Immunocompetent T cells, tumor-suppressing M1 cells, natural killer cells, and other cellular subsets are also present. The TME is further shaped by soluble molecules, extracellular matrix, and other structural components, as well as the presence of blood vessels and ascitic fluid in the peritoneal cavity, which aid in the distribution of cancer cells to the omentum where more lesions soon develop. This review outlines the heterogenous immune cell subsets in the ovarian TME and other structural targets that promote or reduce cancer burden. Most single-agent immune strategies have shown limited efficacy in unselected HGSOC populations due to the complex immune-suppressive nature of the TME. Here, we also discuss novel combination treatments in clinical trials or in clinical practice for HGSOC. Advances in understanding the ovarian TME will reveal new immunotherapy and drug targets for translational medicine and aid in determining effective drug and immunotherapy combinations, which may ultimately lead to improved overall survival in HGSOC.

Background/Objectives: High-grade serous ovarian cancer (HGSOC) is usually discovered in advanced stages and often relapses shortly after initial conventional therapy. Survival in HGSOC patients might be improved with the use of novel immune therapies, which potentiate autologous anti-tumor responses. Dendritic cells (DCs) are potent antigen-presenting cells that can initiate immune responses, activate cytotoxic T cells and drive T-cell differentiation. This pilot trial evaluated the safety and efficacy of a unique DC vaccine (α-DC-1) in relapsed, advanced HGSOC patients with minimal tumor burden. Methods: Monocytes from patient leukaphereses were used to propagate a unique autologous DC, the α-DC-1, generated with granulocyte–macrophage colony-stimulating factor and interleukin-4, pulsed with keyhole limpet hemocyanin (KLH) and tumor lysate (from debulking surgery) on day 5, and matured with a cocktail of cytokines and chemokines on day 6. Mature α-DC-1 were harvested on day 7 and administered intranodally (inguinal nodes) every other week for three doses/cycle for up to three DC vaccine cycles (nine vaccines). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: In 19 patients treated, the median PFS was 9.7 months (95% CI: (5, NA)) and the median OS was 42.2 months (95% CI: (31.2, 68.3)). In 5/19 (26.3%) patients, OS exceeded five years. Administration of six or more vaccines was associated with a significant improvement in PFS. No grade 2 or higher toxicities were noted. Conclusions: Our α-DC-1 vaccine was safe, and 94.2% elicited an immune response to KLH. The long OS, exceeding 5 years in some patients, suggests this DC vaccine may improve survival for some with relapsed HGSOC.