The Evolving Role of Immune Checkpoint Inhibitors in Ovarian Cancer

Background: 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. Immunotherapy has shown promise in other cancers such as melanoma, bladder, lung, leukemia, and breast. Immune checkpoint inhibitors for ovarian cancer ICPIs impede the ability of the tumor to activate checkpoint proteins on the surface of T cells, thereby preventing the cancer from evading immune response and allowing the immune system to generate an antitumor response. Co-stimulatory receptors that promote the activity of T cells include CD28, OX40, GITR, CD137, CD27, and HVEM. Checkpoint receptors that decrease T cell activity include PD-1, CTLA4, TIM-3, BTLA, VISTA, and LAG-3 The ligands that bind to and activate both categories of receptors are commonly found on the surface of other cells, and the ligands for checkpoint receptors tend to be found at a much higher rate on malignant cells. The PD-1 receptor (programmed cell death) suppresses T cell responses and expression of PD-L1 or PD-L2 on the surface of tumor cells and tumor-associated macrophages is therefore a major mechanism of immune evasion. PD-1 is also highly expressed on Tregs, and activation of this checkpoint receptor on Tregs increases their suppressive activity. CTLA4 is another immune checkpoint receptor that is exclusively found on T cells. The CD28 has a competitive receptor for B7 ligand, the cytotoxic T lymphocyte antigen-4 (CTLA-4), which delivers an inhibitory signal. PD-L1/PD-1 receptor B7/CTLA-4 interactions are important immune escape mechanisms, allowing tumor progression. Immune checkpoint blockade therapeutics work by preventing these negative receptor/ligand interactions, and restoring the function of exhausted T cells. In order to prevent the activation of the immune-inhibitory pathways, several monoclonal antibodies are under development. A variety of ICPCs have gained FDA approval, yet the study of ICPIs in gynecologic cancers lags behind other disease sites. Nivolumab (Bristol-Meyers-Squibb) and pembrolizumab (Merck) target PD1.Ipilimumab (Bristol-Meyers- Squibb; targets CTLA-4, with indications in melanoma, urothelial, and lung cancers. Atezolizumab (Genentech-Roche), darvulamab (Astra-Zeneca), and avelumab (EMD-Serono) target PD-L1 and are approved for urothelial/lung cancers, bladder/lung, and for lung/Merckel cell cancers, respectively Toxicities related to ICPIs most commonly include skin (rash, pruritus), gastrointestinal tract (diarrhea), infusion-related reactions, and fatigue, which may limit the clinical effectiveness of this class of drugs. In conclusion, ovarian cancer is an immunogenic disease and currently available data suggest a potential activity of immune checkpoint inhibitors. There are still some points to be addressed.

کلیدواژه ها:

immune checkpoint inhibitors ، ovarian cancer