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Next Generation of Immunotherapy for Melanoma

John M. Kirkwood, Ahmad A. Tarhini, Monica C. Panelli, Stergios J. Moschos, Hassane M. Zarour, Lisa H. Butterfield, Helen J. Gogas

From the University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA; and the First Department of Internal Medicine, University of Athens, Athens, Greece

Corresponding author: John M. Kirkwood, MD, Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Ave, Pittsburgh, PA 15213-2584; e-mail: kirkwoodjm{at}upmc.edu

Purpose: Immunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States.

Design: Tumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed.

Results: The limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies.

Conclusion: The successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

Supported by Pfizer, Berlex, and Bristol-Myers Squibb (J.M.K.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.