Modulation of antitumor immune responses by hematopoietic cytokines

BACKGROUND. Advances in immunotherapy for the treatment of patients with malignant disease have led to increasingly successful use of these methods in the clinical setting. This review presents findings from recent studies that have explored improved methods for the presentation of tumor-associated antigens and for the restoration of tumor specific immune responses using cytokine therapy. METHODS. A review of human clinical trial research on immune cytokines from 1995 (MEDLINE) to the present was conducted. Particular attention was focused on articles that reported results from Phase II or later clinical studies in patients with malignant disease. RESULTS. The defects in cellular immunity commonly seen in patients with malignancies often are expressed as tumor specific anergy. Reversing patient tolerance to tumor antigens may be accomplished by treatment with immunoregulatory cytokines, such as Flt-3 and granulocyte-macrophage-colony stimulating factor, that mature and activate dendritic cells. Published clinical studies indicate that granulocyte-macrophage-colony stimulating factor stimulates antigen-presenting cells and has promising antitumor activity as an adjunct or as stand-alone therapy for patients with malignant disease, including leukemia, melanoma, breast carcinoma, prostate carcinoma, and renal cell carcinoma. CONCLUSIONS. Immune-modulating cytokines may be used alone or in combination with other treatments to help restore immune function, improve response to tumor-associated antigens, and reduce the toxic effects of standard antitumor therapies. The evolving understanding of how dendritic cells regulate immune responses and promising results from published studies of immune-enhancing cytokines in the treatment of patients with malignant disease support the conduct of randomized clinical trials to confirm the clinical benefit of these immunotherapeutic strategies.