Most cytokines (including TNF-α, IFN-γ, IL-2, G-CSF, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) have very short serum half-lives (minutes). The usual subcutaneous route of administration provides slower release into the circulation and a longer duration of action. Each cytokine has its own unique toxicity, but some toxicities are shared. For example, IFN-α, IFN-β, IFN-γ, IL-2, and TNF-α all induce fever, flu-like symptoms, anorexia, fatigue, and malaise.
Interferons are proteins that are currently grouped into three families: IFN-`, IFN-a, and IFN-f. The IFN-α and IFN-β families constitute type I IFNs, ie, acid-stable proteins that bind to the same receptor on target cells. IFN-γ, a type II IFN, is acid-labile and binds to a separate receptor on target cells. Type I IFNs are usually induced by virus infections, with leukocytes producing IFN-α. Fibroblasts and epithelial cells produce IFN-β. IFN-γ is usually the product of activated T lymphocytes.
IFNs interact with cell receptors to produce a wide variety of effects that depend on the cell and IFN types. IFNs, particularly IFN-γ, display immune-enhancing properties, which include increased antigen presentation and macrophage, NK cell, and cytotoxic T-lymphocyte activation. IFNs also inhibit cell proliferation. In this respect, IFN-α and IFN-β are more potent than IFN-γ. Another striking IFN action is increased expression of MHC molecules on cell surfaces. While all three types of IFN induce MHC class I molecules, only IFN-γ induces class II expression. In glial cells, IFN-β antagonizes this effect and may, in fact, decrease antigen presentation within the nervous system.
IFN-α is approved for the treatment of several neoplasms, including hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi’s sarcoma, and for treatment of hepatitis B and C infections. It has also shown activity as an anti-cancer agent in renal cell carcinoma, carcinoid syndrome, and T-cell leukemia. IFN-β is approved for use in relapsing-type multiple sclerosis. IFN-γ is approved for the treatment of chronic granulomatous disease and IL-2, for metastatic renal cell carcinoma and malignant melanoma. Clinical investigations of other cytokines, including IL-1, -3, -4, -6, -10, -11, and -12, are ongoing. Toxicities of IFNs, which include fever, chills, malaise, myalgias, myelosuppression, headache, and depression, can severely restrict their clinical use.
TNF-α has been extensively tested in the therapy of various malignancies, but results have been disappointing due to dose-limiting toxicities. One exception is the use of intra-arterial high-dose TNF-α for malignant melanoma and soft tissue sarcoma of the extremities. In these settings, response rates greater than 80% were noted.
Denileukin diftitox is IL-2 fused to diphtheria toxin, used for the treatment of patients with CD25+ cutaneous T-cell lymphomas. IL-12 and GM-CSF have also shown adjuvant effects with vaccines. GM-CSF is of particular interest because it promotes recruitment of professional antigen-presenting cells such as the dendritic cells required for priming naive antigen-specific T-lymphocyte responses. There are some reports that GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer.