Immunotherapy for Ovavian Cancer

Immunotherapy for ovavian cancer could be effective as ovavian cancer cells express immunogenic tumor-associated antigens that elicit detectable, specific immune responses. The positive correlation between ovavian cancer survival and tumor infiltration with CD8+ T cells is compelling evidence that anti-tumor immune surveillance is a critical dictate of clinical outcomes in ovavian cancer. Despite abundant evidence that anti-tumor immunity in ovavian cancer could be effective, immune-based ovavian cancer therapies have generally been only modestly successful, at best.

Anti-milk fat globulin-1: The first therapeutic antibodies to treat human ovavian cancer were anti-human milk fat globulin-1 antibodies radiolabeled and injected into the peritoneum.
Farletuzumab: Farletuzumab is a humanized anti-folate receptor-α antibody thought to function not through blocking folate transport but through antibody dependent cellular cytotoxicity.
Catumaxomab: Catumaxomab is a trifunctional antibody that kills EpCAM-expressing tumor cells, the primary cause of malignant ascites.
Anti-CTLA4: Ipilimumab and tremelimumab are fully human IgG1 or IgG2 antibodies, respectively, that antagonize the CTLA-4 immune checkpoint. Ipilimumab is FDA-approved to treat metastatic or unresectable melanoma and is the first standard-of-care immune checkpoint inhibitor. Anecdotal reports of ovavian cancer responses to ipilimumab and pre-clinical findings prompted an ongoing phase II trial of ipilimumab for platinum-resistant ovavian cancer (NCT01611558). Ipilimumab can cause significant autoimmune side effects. Tremelimumab (in phase III trials for melanoma) could have similar efficacy with reduced toxicities.
Anti-PD-L1: BMS-936559 is a fully human IgG4 monoclonal antibody that blocks PD-L1 from binding its two known receptors PD-1 and CD80.
Oregovomab: CA-125 was targeted in vivo by the murine IgG1 monoclonal antibody oregovomab.
Abagovomab: Abagovomab is an anti-idiotypic CA-125 murine monoclonal antibody[41] that induces anti-CA-125 antibodies.
Volociximab: Volociximab is a chimeric IgG4 monoclonal antibody against AAB1, a component of α5β1 integrin that is anti-angiogenic.
Amatuximab: Mesothelin is a tumor differentiation antigen over-expressed in certain cancers including those of ovary, pancreas and mesothelium. Amatuximab is a chimeric anti-mesothelin monoclonal antibody.
Siltuximab: IL-6 in an important immunopathologic cytokine in distinct tumors and plays diverse immunopathogenic roles in ovavian cancer. Siltuximab is an anti-IL-6 antibody being tested as treatment for various carcinomas, hematologic malignancies and tumor cachexia.
Tocilizumab: Tocilizumab is a humanized anti-IL-6 receptor antibody being tested for cancer cachexia and is used to mitigate cytokine release symptoms in adoptive T cell therapy.
Anti-CD137: CD137 (4-1BB) is a stimulatory T cell co-receptor that enhances T cell proliferation and cytolytic activity.

Interferon-α: Interferon-α is the principal type I interferon tested for human anti-cancer activity. Intraperitoneal interferon-α to treat OC was first assessed in the early 1980's.
Interferon-γ: Interferon-γ was used to treat ovavian cancer by 1992, and by 1996, intraperitoneal interferon-γ elicited some encouraging preliminary results.
Interleukin (IL)-2: IL-2, a T cell growth and activator factor, exerts modest anti-cancer activity in melanoma and renal cell carcinoma, among other cancers. IL-2 at low doses was combined with retinoic acid in an ovavian cancer trial.
Tumor necrosis factor (TNF)-α: Tumor necrosis factor (TNF)-α.
IL-18: Recombinant IL-18 is an immunostimulatory cytokine that boots antitumor immunity in combination with pegylated liposomal doxorubicin in mouse models.

Many ovavian cancer patients have easily detectable numbers of functional tumor antigen specific T cells, suggesting that augmenting tumor-specific immunity could lead to improved clinical benefits. A number of tumor-associated antigens have been detected in ovavian cancer, any of which potentially could help elicit beneficial anti-tumor- immunity. These tumor-associated antigens include HER2/neu, MUC1, NY-ESO-1, membrane folate receptor, folate binding protein (gp38), TAG-72, mesothelin, sialyl-Tn, milk fat globulin-1, OA3, P53, Carcinoembryonic antigen glypican-3 (GPC3) and Carcinoembryonic antigen (CEA).

The adoptive cell transfers in ovavian cancer include Dendritic cells (DC), T cells, and Oncolytic viruses.
Over the next several years we expect that important advances in ovavian cancer immunotherapy will be made, leading to important phase II and III trials.