Immunotherapy Advances for Epithelial Ovarian Cancer

Abstract

New treatment modalities are needed in order to improve the prognosis of women diagnosed with epithelial ovarian cancer (EOC), the most aggressive gynecologic cancer type. Most ovarian tumors are infiltrated by immune effector cells, providing the rationale for targeted approaches that boost the existing or trigger new anti-tumor immune mechanisms. The field of immuno-oncology has experienced remarkable progress in recent years, although the results seen with single agent immunotherapies in several categories of solid tumors have yet to extend to ovarian cancer. The challenge remains to determine what treatment combinations are most suitable for this disease and which patients are likely to benefit and to identify how immunotherapy should be incorporated into EOC standard of care. We review here some of the most promising immune therapies for EOC and focus on those currently tested in clinical trials.

Keywords: CAR T cells; cancer vaccines; epithelial ovarian cancer; immune checkpoint inhibitors; immune therapy; oncolytic viruses.

Figure 1

Diagram summarizing the main immune mechanisms targeted by immune therapy in epithelial OC. Induction of tumor cytolytic effects (via chemotherapy of oncolytic viruses) leads to the release of tumor antigens that are taken up by antigen presenting cells, primarily dendritic cells. Following intracellular processing, peptide epitopes are presented to MHC class I and class II restricted T cells. Tumor antigen primed, activated CD8 T cells express cytotoxic markers IFN-g, Gzm B and Prf, which are essential for tumor cell killing. Tumor antigen-loaded DC vaccines (using antigens such as MUC1, MUC16, NY-ESO-1, p53, mesothelin, FRa, WT1) have been developed for EOC treatment. To become effective against tumor cells, the tumor antigen specific, activated effector (especially CD8) T cells need to overcome tumor-induced immune suppressive interactions, including those occurring via immune checkpoint molecules like PD-1 (on T cells) and PD-L1 (on tumor cells). Immune checkpoint blockade (ICB) using blocking antibodies (a-PD-1, a-PD-L1, a-CTLA-4) can release the “break” on and revert “exhaustion” of TILs. Cells such as MDSC and Tregs carry out additional immune suppressive effects that can be targeted via VEGF blockade and CTLA-4 blockade, respectively. Newly engineered CAR T cells recognize tumor antigens in a non-MHC restricted manner and are cytotoxic against tumor cells. Abbreviations: CAR—chimeric antigen receptor; EOC—epithelial ovarian cancer; FRα—folate receptor alpha; Gzm B—granzyme B; MDSC—myeloid derived suppressor cells; MHC- major histocompatibility complex; MUC1—mucin 1; Prf—perforin; TAM—Tumor associated macrophages; TCR—T cell receptor; TILs—tumor infiltrating lymphocytes; Treg—regulatory T cells; VEGF—vascular endothelial growth factor; WT1—Wilms tumor 1.