Abstract
Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate the immune system of cancer patients has been an important treatment modality and continues to be a key contributor to current clinical cancer research. Interferon alpha (IFNα) is approved for adjuvant treatment of completely resected high-risk melanoma patients and several refractory malignancies. High-dose interleukin-2 (HDIL-2) is approved for treatment of metastatic renal cell cancer and melanoma, but both agents are currently less commonly used with the development of newer agents. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN gamma (IFNγ), IL-7, IL-12, and IL-21 were evaluated in clinical trials and remain part of certain investigational trials. The initial single-agent clinical trials with the long-awaited IL-15 have been completed and combination trials with antitumor antibodies or checkpoint inhibitors (CPIs) have been initiated. However, cytokines in monotherapy have not fulfilled the promise of efficacy seen in preclinical experiments. They are often associated with severe dose-limiting toxicities that are manageable with appropriate dosing and are now better understood to induce immune-suppressive humoral factors, suppressive cells, and cellular checkpoints, without consistently inducing a tumor-specific response. To circumvent these impediments, cytokines are being investigated clinically with new engineered cytokine mutants (superkines), chimeric antibody-cytokine fusion proteins (immunokines), anticancer vaccines, CPIs, and cancer-directed monoclonal antibodies to increase their antibody-dependent cellular cytotoxicity or sustain cellular responses and anticancer efficacy. In this review, we summarize current knowledge and clinical application of cytokines either as monotherapy or in combination with other biological agents. We emphasize a discussion of future directions for research on these cytokines, to bring them to fruition as major contributors for the treatment of metastatic malignancy.