Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.

Keywords: Cancer vaccine; cytotoxic T-lymphocyte antigen-4 (CTLA-4); immune checkpoint; immunotherapy; programmed cell death ligand-1 (PD-L1); programmed death-1 (PD-1).

Figure 1

Model for the combination of vaccine-based therapy and immune checkpoint inhibitors. (A) Pancreatic ductal adenocarcinoma (PDA) is infiltrated primarily with M2 macrophages (M2), type 2 T helper cells (Th2), myeloid-derived suppressive cells (MDSC), and regulatory T cells (Treg) but with few effector T cells (Teffs). Lacking PD-1/PD-L1 targets, PDA does not respond to single-agent checkpoint inhibitor treatments, such as anti-PD-1 or PD-L1 therapeutic antibodies (anti-PD-1/PD-L1 Ab). (B) Following vaccine-based therapy, vaccine-induced Teffs are infiltrated into PDA; however, PD-L1/PD-L1-mediated immune checkpoint pathways are also induced. By targeting PD-L1/PD-L1 signals on PDA tumor cells and monocytes (Mo) induced by vaccine-based therapy, anti-PD-1/PD-L1 therapeutic antibodies enhance vaccine-induced antitumor immune responses.