994 Clinical Advances in Hematology & Oncology Volume 5, Issue 12 December 2007 Immunotherapy of Advanced or Metastatic Melanoma Jonathan Cebon, MBBS, FRACP, PhD, Craig Gedye, BSc(Hons), MBChB, FRACP Thomas John, MBBS, FRACP, and Ian D. Davis, MBBS (Hons), FRACP, PhD, FAChPM Abstract: Melanoma is often evaluated for the development of anticancer immunotherapeutics. Fascinating immune and clinical responses in small numbers of patients have prompted various approaches, ranging from nonspecific immune stimulation to therapies that target specific anti- gens. Unfortunately, these immune therapies have often shown limited success and objective responses have been seen in only a modest subset of patients. The challenge has been to identify factors that can lead to more consistent clinical benefit and to develop strategies to overcome the obstacles to successful antitumor immunity. Over the last 15 years many immune targets have been identified in cancers and the mechanisms underpinning clinical responses have become better understood. Further- more, new ways to manipulate anticancer immunity are making it possible to overcome cancer immune evasion and subversion. New therapeutic strategies are resulting from these emerging insights into the relationship between melanoma and the host immune response. Melanoma as an Immune Target Melanoma has become the malignancy most commonly investigated with immunotherapeutic approaches in preclinical models and in the clinical setting. A number of early observations suggested that immune recogni- tion might alter the natural history of the disease: regression of primary melanomas, implying an immunologic effect; rarer spontaneous remis- sions of metastatic disease; and favorable clinical outcomes (regression or prolonged natural history) in association with autoimmune phenomena such as melanoma-associated retinopathy or vitiligo. 1 Tumor-infiltrating lymphocytes have also been associated with a more favorable clinical course. 2 Nonetheless immune therapies have shown limited success, and objective responses to therapy have been seen in only a modest subset of patients. he challenge has been to identify factors that can lead to more consistent clinical benefit and to develop strategies to overcome the obstacles to successful antitumor immunity. Over the last 15 years, many immune targets have been identified in cancers and the mechanisms underpinning these clinical responses have become better understood. A clearer understanding of the relationship between melanoma and the Dr. Cebon is Professor of Medicine, University of Melbourne, and Director of Medical Oncology. He heads the Cancer Vaccine Group. Dr. Davis is a Medical Oncologist and Associate Professor of Medicine. Dr. Gedye and Dr. John are Medical Oncologists. All are based at the Ludwig Institute for Cancer Research, Center for Clinical Sciences at the Austin Hospital, Melbourne, Australia. Address correspondence to: Jonathan Cebon, Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences Austin Hospital, Studley Road, Heidelberg, VIC 3084 Australia Phone: +613 9496 5462 Fax: +613 9457 6698 E-mail: jonathan.cebon@ludwig.edu.au Keywords Melanoma, immunotherapy, antigen, T cell