Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment

Immunotherapy has caused a paradigm shift in the treatment of several malignancies, particularly the blockade of programmed death-1 (PD-1) and its specific receptor/ligand PD-L1 that have revolutionized the treatment of a variety of malignancies, but significant durable responses only occur in a small percentage of patients, and other patients failed to respond to the treatment. Even those who initially respond can ultimately relapse despite maintenance treatment, there is considerable potential for synergistic combinations of immunotherapy and chemotherapy agents with immune checkpoint inhibitors into conventional cancer treatments. The clinical experience in the use of cytokines in the clinical setting indicated the efficiency of cytokine therapy in cancer immunotherapy. Combinational approaches to enhancing PD-L1/PD-1 pathways blockade efficacy with several cytokines such as interleukin (IL)-2, IL-15, IL-21, IL-12, IL-10, and interferon-alpha (IFN-alpha) may result in additional benefits. In this review, the current state of knowledge about PD-1/PD-L1 inhibitors, the date in the literature to ascertain the combination of anti-PD-1/PD-L1 antibodies with cytokines is discussed. Finally, it is noteworthy that novel therapeutic approaches based on the efficient combination of recombinant cytokines with the PD-L1/PD-1 blockade therapy can enhance antitumor immune responses against various malignancies.