Immunomodulating Therapies

Cytokine Therapy

The experimental and clinical applications of cytokines, as biologic response modifiers and therapeutic agents, have been greatly expanded in recent years. Some cytokines, such as tumor necrosis factor and interferon alfa, have direct antitumor activity. Other cytokines affect tumor immune responses by lymphokine-activated killer cells, tumor-infiltrating lymphocytes, and activated natural killer cells. Cytokines have been used to activate immune cells ex vivo prior to adoptive transfer or have been given concurrently with activated effector cells. Phase I and phase II trials of cellular adoptive therapy, with IL-2 activated killer cells, for the treatment of renal cell carcinoma and melanoma have demonstrated feasibility and regression of metastasis in some patients. Modest results, significant morbidity, and high cost have hampered widespread adoption of these techniques.

Interferon alfa is used in hairy cell leukemia, chronic myelogenous leukemia, Kaposi's sarcoma, and chronic active hepatitis B and C. Interferon beta is used for multiple sclerosis and interferon gamma for the treatment of chronic granulomatous disease. Constitutional symptoms are common with cytokine therapy, and in some instances toxicity is considerable.

Tumor Necrosis Factor (TNF) Antagonists

Several approaches have been developed to mitigate the biologic effects of TNF, a cytokine produced by macrophages and other antigen-presenting cells. TNF activates gene expression of proinflammatory mediators, up-regulates adhesion molecule expression, stimulates neutrophil function, possesses antitumor and antiviral activity, and is an endogenous pyrogen. In addition to its proinflammatory properties, TNF has been associated with induction of matrix metalloproteanases, alterations in vascular permeability and angiogenesis, leading to bone resorption, cartilage degradation, and rheumatic joint disease. Two molecules have been designed to inhibit binding of TNF to its cellular receptor and thereby reduce its cellular and biologic effects. Etanercept is a dimeric construct - containing the soluble TNF receptor - joined to the Fc domain of a human IgG molecule. Infliximab is a chimeric antibody molecule containing a human Fc domain and a murine variable region. Both are disease-modifying antirheumatic drugs (DMARDs) that have been shown to slow joint destruction and markedly decrease symptoms of rheumatoid arthritis. Etanercept has shown efficacy in ankylosing spondylitis. It must be administered by subcutaneous injection twice weekly; infliximab is given intravenously every 2 months.

Soluble IL-1 Receptor Antagonist

Anakinra, a recombinant, nonglycosylated soluble IL-1 receptor antagonist, competitively inhibits the binding of IL-1 to its cellular receptor. IL-1 is a major immunomodulatory cytokine, proinflammatory agent, and endogenous pyrogen. Through receptor blockade, anakinra has proved to be anti-inflammatory and efficacious in the treatment of rheumatoid arthritis.