Review 10.1586/14737140.6.8.1305 © 2006 Future Drugs Ltd ISSN 1473-7140 1305 www.future-drugs.com Vaccination: role in metastatic melanoma Lorenzo Pilla, Roberta Valenti, Andrea Marrari, Roberto Patuzzo, Mario Santinami, Giorgio Parmiani and Licia Rivoltini † † Author for correspondence Istituto Nazionale per lo Studio e la Cura dei Tumori, Unit of Melanoma and Sarcoma, Via Venezian 1, 20133 Milan, Italy Tel.: +39 022 390 3245 Fax: +39 022 390 2154 licia.rivoltini@istitutotumori.mi.it KEYWORDS: adjuvants, antigens, heat-shock proteins, melanoma, peptides, vaccine Based on the poor impact on overall survival obtained by systemic chemotherapy in metastatic melanoma and the identification of many melanoma antigens recognized by T cells, in the last decade many efforts have been devoted to the development of active specific immunotherapy as a promising systemic treatment for this neoplastic disease. A number of Phase I–II clinical trials have been performed with different vaccination approaches that included whole tumor cells, antigen peptides, antigen-pulsed dendritic cells, recombinant viruses, plasmids or naked DNA, and heat-shock proteins. Despite some promising immunological and clinical results obtained in these studies, melanoma- specific vaccines have altogether failed to prove their efficacy in the few large Phase III randomized clinical trials performed. Nonetheless, the possibility of activating the human immune system to recognize and destroy tumor cells remains a challenging investigative field, considering that the new knowledge of the intricate cellular and molecular mechanisms that regulate the immune function and tumor–host interactions may allow the development of new clinically relevant melanoma vaccination strategies. Expert Rev. Anticancer Ther. 6(8), 1305–1318 (2006) The incidence of malignant melanoma is increasing at a faster rate than any other cancer in the USA and Western European countries, with an incidence ranging between 6.5/100,000 inhabitants in Italy and 51.6/100,000 inhabitants in Australia [1]. While primary lesions are curable with appropriate surgical resection, systemic meta- static melanoma is associated with poor prog- nosis, with a median survival ranging from 6 to 9 months and 5-year survival rates of only 1–2% [2]. Although the excision of localized distant metastasis may lead to durable benefits in a subgroup of patients, most patients with meta- static melanoma require a systemic treatment, which has been mainly represented by cyto- toxic chemotherapy. T he most widely used chemotherapeutic agent for metastatic melanoma is dacarbazine (DT IC), alone or in combination with other chemotherapeutic drugs. Although these regimens have produced response rates ranging between 30 and 50% in single-institution Phase II trials, subsequent large Phase III randomized studies showed that the same chemotherapy regimens had no impact on overall survival [3]. Similarly, while several Phase II trials in which chemotherapy was given in association with the systemic administration of cytokines, such as high dose interleukin (IL)-2 or interferon (IFN)-α (biochemotherapy), obtained encouraging response rates and progression-free survival, subsequent large Phase III studies failed to demonstrate advantages in overall survival [4,5]. Owing to the relative resistance of melanoma cells to chemotherapy, this tumor has tradition- ally been a disease in which novel systemic treatment options have been investigated, including active specific immunotherapy. Immunology of melanoma Early evidence that melanoma cells could be a target for the immune response came from clinical and epidemiological observations show- ing that, in a minority of patients, primary CONTENTS Immunology of melanoma Vaccines Expert commentary & five-year view Key issues References Affiliations For reprint orders, please contact reprints@future-drugs.com