The strategy to treat cancer by modulating the immune response has been the subject of research for the last twenty years, including the use of vaccines or activating cytokine therapies. Recently, in the last few years, a breakthrough was achieved by the discovery of immune checkpoints, particularly the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programed cell death receptor-1 (PD-1), or programed cell death ligand-1 (PD-L1). The blockade of the pathway for PD-L1 and PD-1 has been used therapeutically for the treatment of a variety of cancers and has achieved long-term remissions in some patients and there are a number of active clinical trials ongoing that target PD-1 and PD-L1. However, a number of cancers are resistant to checkpoint inhibitor-based immunotherapy. The majority of the drugs used for the blockade of the PD-1 and PD-L1 pathways are humanized antibodies. The fact that there have been immune related toxicities associated with PD pathway blockade using the current technologies suggests that an alternative approach may be necessary.