Immunotherapy in ovarian cancer: fake news or the real deal?

Abstract

Cancer immunotherapy has emerged as one of the most promising approaches in oncology, and comprises the activation of the immune system to induce tumor immune surveillance or to reverse the tumor immune escape. Different therapeutic strategies for ovarian carcinoma have evolved over the years. Already 30 years ago, the first clinical studies focused on modulating the tumor cytokine network with special attention to interferon-mediated immune responses. With the exploration of specific tumor antigens such as NY-ESO-1, which is expressed in ovarian carcinoma and other malignancies, the development of therapeutic cancer vaccines has been pursued initiating the era of personalized anti-cancer medicine. Almost at the same time, the adoptive transfer of genetically modified autologous tumor-reactive T-cells occurred, but response rates in ovarian carcinoma were disappointing. Today, probably the most promising therapeutic approach in this context is the blockade of immune checkpoints, such as programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) or cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4), which has demonstrated impressive response rates in malignant melanoma and non-small cell lung cancer. Despite increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. Here, we summarize different immunotherapy approaches in ovarian cancer and discuss why immunotherapy in ovarian cancer is still in its infancy.

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…For detailed reviews of antibody-based immunotherapies for ovarian cancer see Tse et al, 2014 [ 200 ] and Drerup et al, 2015 [ 201 ]. For more recent reviews of immune therapies for ovarian cancer with engineered T-cells, TCRs, and CAR-T cells see Marth et al, 2019 [ 8 ]; Fan et al, 2018 [ 53 ]; Rodriguez et al, 2018 [ 73 ]; Zhu et al, 2017 [ 202 ]; Rodriguez-Garcia et al, 2017 [ 203 ]; Gaillard et al, 2016 [ 52 ]; Alipour et al, 2016 [ 204 ]. These include summaries of recruiting and ongoing clinical trials targeting immune checkpoint inhibitors or various antigens including, NY-ESO-1, HER2, FR-alpha, MSLN, MUC16 (CA125), EGFR, CD133, CEA, NKG2D, MAGE-A4, WT-1, and p53.…”

“…Serious side-effects, however, were also seen in some patients, particularly inflammation [ 290 ]. Such immune-related toxicities are thought to be due to indiscriminate activation of auto-reactive T-cells, which are usually supressed via these molecules [ 8 ]. Only 2 patients out of 40 with recurrent platinum sensitive ovarian cancer completed a phase 2 clinical trial with Ipilimumab monotherapy (NCT01611558), with failure to complete mostly due to study drug toxicity or disease progression [ 291 ].…”

“…Observations of tumour infiltrating lymphocytes (TILs) that are associated with improved clinical outcomes in ovarian cancer, and recognition that it is an immunogenic disease [ 5 , 6 , 7 ], have made the concept of ovarian cancer immunotherapy increasingly attractive. However, it has been highlighted recently that immunotherapy for ovarian cancer is still in its infancy, [ 8 ], with only one monoclonal antibody therapy (bevacizumab), targeting angiogenesis in the tumour microenvironment (TME), being approved for its’ treatment [ 9 ]. Recent cancer immunotherapy advances tend to combine several agents and strategies, including anti-angiogenesis with more standard cancer treatments, for therapeutic synergy [ 10 ].…”

Resistance to chemotherapy and anti-angiogenic therapy in ovarian cancer

“…Today, probably another promising therapeutic approach in this context is the blockade of immune checkpoints, such as programmed cell death 1 (PD-1), its ligand PD-L1 or cytotoxic T-lymphocyte associated protein 4 (CTLA4), which demonstrated impressive response rates in malignant melanoma and non-small-cell lung carcinoma (NSCLC). Considering this and a positive expression of check point molecules in OC which is associated with clinical outcome [41] many clinical studies investigate check point inhibitors in OC, especially platinum-resistant or recurrent OC [42]. Various simultaneous anti-angiogenics may improve the therapeutic benefit and counteract compensatory escape mechanisms [43].…”

Development and validation of an immune-related prognostic signature for ovarian cancer based on weighted gene co-expression network analysis

“…Recently, studies showed that immune responses have close relationships with ovarian cancer progression [6] . At present, some pre-clinical trials targeting immune cells in the ovarian cancer microenvironment have been performed.…”