Elsevier

Gynecologic Oncology

Volume 142, Issue 2, August 2016, Pages 349-356
Gynecologic Oncology

Review Article
Ovarian cancer and the immune system — The role of targeted therapies

https://doi.org/10.1016/j.ygyno.2016.05.007Get rights and content

Highlights

  • Ovarian cancer therapies do not account for interactions with the immune system.

  • Molecular targets can augment immune response or negate immunosuppression.

  • FDA approved immunomodulatory agents show promise in ovarian cancer.

Abstract

The majority of patients with epithelial ovarian cancer are diagnosed with advanced disease. While many of these patients will respond initially to chemotherapy, the majority will relapse and die of their disease. Targeted therapies that block or activate specific intracellular signaling pathways have been disappointing. In the past 15 years, the role of the immune system in ovarian cancer has been investigated. Patients with a more robust immune response, as documented by the presence of lymphocytes infiltrating within their tumor, have increased survival and better response to chemotherapy. In addition, a strong immunosuppressive environment often accompanies ovarian cancer. Recent research has identified potential therapies that leverage the immune system to identify and destroy tumor cells that previously evaded immunosurveillance mechanisms. In this review, we discuss the role of the immune system in ovarian cancer and focus on specific pathways and molecules that show a potential for targeted therapy. We also review the ongoing clinical trials using targeted immunotherapy in ovarian cancer. The role of targeted immunotherapy in patients with ovarian cancer represents a field of growing research and clinical importance.

Introduction

Epithelial ovarian cancer (EOC) remains the deadliest gynecologic malignancy in the United States, with an estimated 21,000 new cases and 14,000 deaths in 2015 [1]. Advances in traditional cytotoxic chemotherapy such as intraperitoneal administration and dose-dense therapeutic regimens are improving response rates, as are novel agents like bevacizumab, but these treatments are failing to significantly affect overall survival [2]. Moreover, patients often develop resistance to chemotherapy. Thus, there is an urgent need to identify novel treatments, such as immune-directed therapies, to replace traditional cytotoxic chemotherapy. The objective of this review is to discuss the immune response in ovarian cancer and to review targeted therapies currently used to enhance the immune response against EOC. This focus precludes significant discussion regarding viral and cellular based therapies, the latter having been recently reviewed [3].

Section snippets

The immune system and cancer

Although one might assume that the immune system cannot recognize or eliminate cancer cells because they are a form of “self”, rather than foreign invaders like viruses or bacteria, new data clearly show that immunodeficient mice are much more susceptible to malignancy [4], [5], implying that adaptive immunity is important for keeping tumor cells in check. In fact, a variety of immune cells, particularly T cells and natural killer (NK) cells, are important for the identification and cytotoxic

Tumor infiltrating lymphocytes

Similar to other solid tumors , the role of the immune response in ovarian cancer is well documented [23], [24], [25]. A selection of key studies is provided in Table 1. For example, there is a positive correlation between the number of tumor infiltrating lymphocytes (TILs) and overall survival [23], a phenomenon that is confirmed in multiple studies [24], [26]. In particular, the presence of CD8 T cells correlates positively with survival (median survival 55 vs. 26 months in 117 patients) [24].

Blockade of immune checkpoints

Given the wide variety of immunosuppressive mechanisms that impair anti-tumor immunity, it is not surprising that a wide variety of therapeutics are being developed to overcome these immune checkpoints. For example, CTLA4 is an inhibitory receptor on T cells that impairs T cell activation and proliferation and enhances Treg-mediated suppression [80]. A blocking antibody against CTLA4, ipilimumab (Bristol-Myers Squibb), that reverses these effects is now approved for the treatment of metastatic

Conclusions

The knowledge and understanding of the immune response to ovarian cancer continues to grow and guide therapeutic options. The complexity of the system will require thoughtful planning when designing future trials, both in the laboratory and the clinic. Because the preclinical evidence has been encouraging, numerous immunotherapy trials are underway. Immunotherapy benefits from the past decade of targeted therapies. A single pathway inhibitor or activator is unlikely to have a dramatic effect in

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgements

The authors would like to thank Dr. Lyse Norian for her help and support of this review.

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