Immunotherapy of melanoma

Melanoma is considered one of the immunogenic – if not the most immunogenic – malignancies. This is based on several observations. 1. Spontaneous remissions occur occasionally. 2. In about 5% of melanomas no primary tumour is found. The genetic aberrations of these tumours closely resemble those of cutaneous melanomas, and therefore are suggestive of spontaneous regressions of the primary tumours. 3. Both primary tumours and metastases often have brisk lymphocytic infiltrates, a phenomenon that is correlated with better outcome. 4. Studies of isolates of these tumour-infiltrating T lymphocytes have revealed that a proportion of these cells recognise melanoma antigens. 5. Melanomas respond to immunotherapy. These observations have led to over 30 years of research on immunotherapy for melanoma; many of these efforts have failed, with only a few exceptions: interleukin-2 (IL-2) and to a lesser degree interferon-a (IFN-〈). Recently, new developments in immunotherapy have revolutionised this treatment modality. Anti-CTLA4 has received approval from the Food and Drugs Administration (FDA) and the European Medicines Agency (EMA) for the treatment of stage IV melanomas based on the improvement in overall survival in phase III trials, and more recently blockade of PD1/PDL1 interactions has shown objective clinical responses in a stage IV melanoma in early-phase clinical trials. In addition, several independent single-institution phase I/II trials using adoptive cell therapy have shown a consistently high response rate, including durable complete remissions in a substantial percentage of treated patients. Now, for the first time, immunotherapy has moved beyond the treatment of melanoma as both CTLA4 and PD1 blockade have been shown to induce objective responses in other tumour types as well. This chapter will discuss the mechanism of action, clinical efficacy and side effects of IL-2, the novel treatments consisting of the immune checkpoint blockade drugs anti-CTLA4 and anti-PD1 and adoptive cell therapy.