Dual targeting of CD137 co-stimulatory and PD-1 co-inhibitory molecules for ovarian cancer immunotherapy

Abstract

We recently demonstrated that simultaneous targeting of CD137 co-stimulatory and programmed cell death 1 (PD-1) co-inhibitory molecules synergistically induced an anticancer immune response in the ID8 syngeneic orthotopic mouse ovarian carcinoma model. We further showed that the therapeutic efficacy was enhanced by treatment with cisplatin. These findings provide a rationale for evaluating dual targeting of CD137/PD-1 co-signaling molecules in ovarian cancer patients.

Keywords: CD137; PD-1; co-signaling molecules; immunotherapy; monoclonal antibody; ovarian cancer.

Figure 1. Induction of an anticancer immune response by dual targeting of CD137 co-stimulatory and PD-1 co-inhibitory molecules in combination with conventional cancer therapy. Immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tolerogenic dendritic cells (DCs) are present in the tumor microenvironment. Immunosuppressive cells and their associated cell-cell signaling molecules induce functional exhaustion of tumor-recognizing T cells via programmed cell death-1 (PD-1/PD-L1) and other inhibitory pathways. Dual targeting of CD137/PD-1 abolishes the local suppression and leads to functional rescue and expansion of effector T cells that subsequently kill the cancer cells. Combination with radiotherapy, certain chemotherapeutic drugs or cancer vaccines may also expand the population of tumor-reactive T cells relieved from suppression and cause tumor regression.