Abstract

After decades of failure to improve the prognosis of metastatic melanoma patients, the treatment has progressed markedly in recent years due to the development of targeted therapies directed against (mutated) signalling proteins and immunotherapies like monoclonal antibodies (mAb) targeting T cell checkpoint blockade. Melanoma has been always considered one of the most immunogenic tumours, but only the recent improvement in understanding how T cell responses are modulated and which of these mechanisms are used by tumours to escape the immune response have allowed us to achieve clinically meaningful outcomes.

Anti-CTLA4 is the first mAb targeting co-inhibition that has received approval from FDA and EMA for the treatment of stage IV melanomas based on the improvement of overall survival in phase III trials.

More recently, blockade of PD1/PDL1 interactions has shown even higher objective clinical responses in early phase clinical trials. While CTLA-4 is thought to inhibit the early expansion phase, the PD-1/PD-L1 signal alters the effector phase of T cell responses. This is reflected in the response characteristics of CTLA-4 blockade inducing responses late after treatment initiation, while PD-1/PD-L1 blockade can induce early responses. In case of response, both can induce long-term melanoma control or even cure.

Identification of patients benefitting from these promising therapies (biomarker development) and of combinations that increase the response rates (either combinations of different T cell checkpoint modulators or combinations with targeted therapies) will be the challenge for the nearby future.