Immunotherapy in the Treatment of Platinum-Resistant Ovarian Cancer: Current Perspectives

Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer. The gold standard therapeutic approach is a combination of surgery plus chemotherapy. Unfortunately, 80% of patients with EOC suffer recurrence within 2-years and the overall response rate for platinum-resistant epithelial ovarian cancer to cytotoxic chemotherapy or poly-(adenosine diphosphate)-ribose polymerase (PARP) inhibitor is modest. New therapies are needed to improve overall survival. The role of immunotherapy has been established in endometrial and cervical cancers, however its effective use in EOC has been limited due to the intrinsic genomics and micro-immune environment associated with EOC. Studies evaluating immunotherapy, largely immune checkpoint inhibitors (ICI), have shown limited activity, yet some patients benefit greatly. Thus, significant efforts must be devoted to finding new strategies for the use of immunotherapy/immunomodulatory drugs (IMiDs). Immunotherapy has a well-tolerated safety profile; however, cost-effectiveness can be an obstacle. The aim of this article is to review the most recent research into the use of IMiDs in patients with platinum-resistant epithelial ovarian cancer.

Keywords: adverse events; immune checkpoint inhibitors; immunotherapy; ovarian cancer; platinum-resistant; recurrent.

Figure 1

Immunotherapeutic modalities and their application in cancer therapy.

Figure 2

A schematic representation of the tumor microenvironment interplay. Angiogenesis and immune evasion create a microenvironment that supports tumor growth and progression. The MDSCs exert immunosuppressive functions, such as the inhibition of T-effector and natural killer (NK)-cells. M2 macrophages promote immunosuppression by producing cytokines that inhibit T-effectors proliferation and enhance T-regs function. While M1 macrophages and mature dendritic cells activate host immunity and increase Th1 cell recruitment and cytotoxic attack on tumor cells.

Figure 3

A schematic representation of the immune check-point inhibitor mechanisms of action. When PD-L1, a protein on certain cancer cells binds PD-1 a checkpoint transmembrane protein on T-cells, it causes T-cell dysfunction, exhaustion, neutralization thus helping the cancer cell evade the immune system. CTLA-4 is a transmembrane protein expressed on activated T-cell and transmit inhibitory signals to the T-cells. CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes, whereas PD-1 suppresses T-cells later in an immune response, primarily in peripheral tissues.

Figure 4

A schematic representation of the timing of immune-related adverse events (irAEs) in various organ systems.

Figure 5

Tumor-specific cytotoxic T-cells, either isolated from the tumor or in the peripheral blood by leukapheresis, are modulated by genetic engineering and activated. Once they undergo lymphodepleting chemotherapy, they are infused back to the patient.