Checkpoint inhibitors in immunotherapy of ovarian cancer

Ovarian cancer is a cancerous growth arising from numerous parts, mainly the outer lining of the ovary called germinal epithelium. It is the fifth leading cause of cancer-related death among women, which causes more death than any other gynecologic cancers. Usually, early ovarian cancer has no obvious symptoms, and it is sometimes called “silent killer” because the disease often progresses before symptoms arise. Some women experience persistent and non-specific symptoms including bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, or possibly urinary symptoms. The incidence of ovarian cancer increases with age and is most prevalent in the eighth decade of life.

The exact cause of ovarian cancer is unknown. It may be affected by several factors such as, age, body weight, genetic mutation, Lynch syndrome, and postmenopausal estrogen therapy. Currently, the standard treatment for ovarian cancer includes debulking surgery, combining a platinum-based (usually carboplatin) and a taxane-based (usually paclitaxel) therapy. Despite the advances in surgery and chemotherapy over the last 20 years, the patients suffer from severe side effects caused by chemotherapy, and approximately 70–80 % of ovarian cancer might have a recurrence of their disease after first-line chemotherapy. So, the new therapeutic approaches are necessary that can prevent cancer recurrence. A promising and potential approach is found in immunotherapy that can establish a sustained immune system response against recurring cancer cells leading to long-term remissions for ovarian cancer patients.

Cancer immunotherapy
The immune system plays a critical role in cancer control through the dynamic association with tumor cells. The key features of an effective immune response include specificity, stability, trafficking, and antigen spread by which the immune system contributes to the recognition and rejection of malignant cells. Cancer cells express a variety of tumor antigens, which are the targets for an immune response. However, spontaneous immune responses to these antigens are thought to be responsible for the failure of the immune control and thus insufficient for tumor regression. The identification of key molecules that restore the ability of the immune system to fight cancer and infections has led to the development of novel immunotherapeutic approaches for cancer treatment. The goal of cancer immunotherapy is to induce anti-tumor responses, augment immune surveillance, and relieve immune suppression by the host immune system.

Checkpoint inhibitors in ovarian cancer immunotherapy
A promising avenue of immunotherapeutic research in cancer is the use of immune checkpoint inhibitors, which work by targeting molecules that serve as checks and balances in the regulation of immune responses. Immune checkpoints are the co-inhibitory molecules, essential for the maintenance of self-tolerance to prevent immune over-activation and host tissue damage under normal physiologic conditions. But in the diseased condition, cancer takes advantage of this ability to hide from the immune system by manipulating a series of immune escape mechanisms that were developed to evade the host immune system by inhibiting Tcells, which are specific for tumor antigens. Blockade of these immune checkpoints by antibodies or modulated by recombinant forms of ligands or receptors (commonly called checkpoint inhibitors) can significantly enhance anti-cancer immunity or reawaken silenced immune responses. In this review, we have discussed the mechanism of actions and the therapeutic use of checkpoint inhibitors in the treatment of ovarian cancer with clinical success and future management.

Checkpoint inhibitors that augment the anti-cancer immunity include anti-cytotoxic T lymphocyte antigen (CTLA)-4, anti-programmed death (PD)-1, and anti-PD ligand (PD-L1), which have been tested clinically to date. The usage of immune checkpoint inhibitors is a promising systemic therapeutic approach to achieve durable responses or even cure in ovarian cancer and other malignancies (a list of promising checkpoint inhibitors is presented in Table 1). The ultimate goal of these agents is to induce a targeted immune response against cancer cells. The schematic representation of the action of immune checkpoint inhibitors in cancer immunotherapy is presented in Fig. 1.



Dong-hui Wang & Liang Guo & Xiao-hua Wu. Tumor Biol. (2015) 36:33–39