Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

Abstract

This review provides an update on the current use of immune checkpoint inhibitors (ICI) in female gynecologic cancers, and it addresses the potential of these agents to provide therapy options for disease management and long-term remission in advanced disease patients, where surgery, chemotherapy, and/or radiation fail to meet this goal. The topic of immune checkpoint inhibitors (ICI) blocking cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed death-1 (PD-1) axis has come to the forefront of translational medicine over the last decade for several malignancies. The text will focus primarily on a discussion of ovarian cancer, which is the most frequent cause of death of gynecologic cancers; endometrial cancer, which is the most often diagnosed gynecologic cancer; and cervical cancer, which is the third most common female gynecologic malignancy, all of which unfavorably alter the lives of many women. We will address the critical factors that regulate the outcome of these cancer types to ICI therapy, the ongoing clinical trials in this area, as well as the adverse immune responses that impact the outcome of patients given ICI regimens.

Keywords: cervical cancer; clinical trials; combination therapy; disease improvement; endometrial cancer; gynecologic cancers; immune checkpoint inhibitors; immune-related toxicity; ovarian cancer.

Figure 1

Representative schema of interactions at immune checkpoints. Tumor-associated antigens or neo-antigens are presented by the major histocompatibility complex (MHC) to T cells (T-cell receptor, TCR). The binding of CD28 on T cells to CD80/CD86 (B7-1/B7-2) on antigen-presenting cells (APC) results in heightened immune responses or anti-tumor immunity. The cross-linking of cytotoxic T lymphocyte associated protein-4 (CTLA-4) on T cells to CD80/CD86 on APC results in an inhibition of T cell responses. Programmed death-1 (PD-1) on T cells co-ligating with PD-L1 on APC or on tumor cells results in inhibitory or immune-suppressive responses in the tumor microenvironment.