Abstract
Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC.
Highlights
Epithelial ovarian cancer (EOC) is the first cause of death among gynecological neoplasms and the fifth cancer-related cause of death for women in advanced countries [1]
In a murine ovarian cancer model Higuchi and colleagues [58] demonstrated that the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, but not the inhibition of the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway, synergize with poly ADP-ribose polymerase (PARP)-inhibitors increasing long term survival in the majority of mice (p < 0.0001)
Immune checkpoint inhibitors may improve clinical outcome, but before adding them to our therapeutic options several questions need to be addressed: (1) Do we have reliable predictors of response in EOC? (2) Are there subgroups more likely to benefit from immune checkpoint inhibitors? (3) Is there an optimal clinical setting? (4) Is it better to use checkpoint inhibitors alone or in association with other agents? (5) Is there a possible role for PD-L1/L2 in early detection of ovarian cancer?
Summary
Epithelial ovarian cancer (EOC) is the first cause of death among gynecological neoplasms and the fifth cancer-related cause of death for women in advanced countries [1]. Hamanishi and colleagues [34] observed a significant inverse correlation between the intraepithelial CD8+ T lymphocyte count and the expression of PD-L1 in tumor cells They reported a significantly worse prognosis for patients with higher levels of PD-L1 in tumor cells. Varga and colleagues [51] presented the interim first results of a phase Ib trial, evaluating safety and antitumor activity of pembrolizumab (formerly known as lambrolizumab), another anti-PD-1 antibody, in patients with PD-L1-positive advanced solid tumors (PD-L1 expression ě1%). In 2012 Brahmer et al [52] treated 207 patients with advanced solid tumors, including 17 women with ovarian cancer, with BMS-936559, a fully-human IgG4 antibody targeting PD-L1. The most frequent adverse events were fatigue, nausea, and diarrhea [53]
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