Current Advances in PD-1/PD-L1 Blockade in Recurrent Epithelial Ovarian Cancer

Abstract

Immunotherapies have revolutionized the treatment of a variety of cancers. Epithelial ovarian cancer is the most lethal gynecologic malignancy, and the rate of advanced tumor progression or recurrence is as high as 80%. Current salvage strategies for patients with recurrent ovarian cancer are rarely curative. Recurrent ovarian cancer is a "cold tumor", predominantly due to a lack of tumor antigens and an immunosuppressive tumor microenvironment. In trials testing programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) blockade as a monotherapy, the response rate was only 8.0-22.2%. In this review, we illustrate the status of cold tumors in ovarian cancer and summarize the existing clinical trials investigating PD-1/PD-L1 blockade in recurrent ovarian cancer. Increasing numbers of immunotherapy combination trials have been set up to improve the response rate of EOC. The current preclinical and clinical development of immunotherapy combination therapy to convert an immune cold tumor into a hot tumor and their underlying mechanisms are also reviewed. The combination of anti-PD-1/PD-L1 with other immunomodulatory drugs or therapies, such as chemotherapy, antiangiogenic therapies, poly (ADP-ribose) polymerase inhibitors, adoptive cell therapy, and oncolytic therapy, could be beneficial. Further efforts are merited to transfer these results to a broader clinical application.

Keywords: cold tumor; immunotherapy; programmed death ligand 1 (PD-L1); programmed death-1 (PD-1); recurrent ovarian cancer.

Figure 1

Immunotherapies based on anti-PD-1/PD-L1 pathway antibodies. (A) Inhibition of T cell activity caused by binding programmed death ligand 1 (PD-L1) to programmed death (PD-1). (B) Activization of T cell activity by using anti-PD-1 or anti-PD-L1 antibodies. The cancer cells become immunogenic again. This leads to recognition of tumor cells by T cells and final elimination by the host immune system.

Figure 2

Flow diagram of reference identification and selection.

Figure 3

Tumor microenvironment of “hot” and “cold” cancer. (A) High activities of effector immune cells, such as CD8+ effector T cells, tumor-associated macrophages (TAM), dendritic cells (DC), IL+17 T cells (TH17) and CD4+ activated T cells. (B) High activities of Myeloid-derived suppressor cells (MDSCs), Tregs and CAFs, low activities of CTLs(CD8+)and few recruitment of dendritic cells(DCs). Since the edge of the tumor is in a state of chronic hypoxia, immune cells could migrate from the edge toward the center of tumor, making the core of tumor immunologically hot.

Figure 4

Tumor microenvironment related immunotherapeutic strategies in ovarian cancer. The graph shows multiple therapies combined with PD-1/PD-L1 blockades to boost the immune response, including chemotherapy, antiangiogenic therapy, PARP inhibitor, adoptive ​cell​ therapy, vaccine-​based ​therapy, oncolytic therapy and T cell ​immunomodulators.