[Unblocking antitumor immune response: novel possibilities for the immunotherapy of melanoma]

Recent advances in tumor immunology, a better understanding of mechanisms regulating the immune response has led to experimental and clinical testing of a novel type of immunotherapeutics: antibodies blocking negative regulatory mechanisms of T-cell activation [corrected]. The application of the CTLA-4 antagonist ipilimumab, the prototype of this new class of immune stimulating agents, represents the first treatment that resulted in significant prolongation of the survival of metastatic melanoma patients in randomized, controlled trial, leading to the approval of its use for the therapy of these patients in 2011. Together with the BRAF inhibitor vemurafenib, which was also approved in 2011, ipilimumab has changed the standard therapy of metastatic melanoma, and also paved the way for other agents aiming at influencing immune regulating molecules, of which antibodies blocking the PD-1 pathway also showed promising clinical activity. According to clinical experience collected so far, these agents induce objective tumor response in a relatively small proportion of patients, with a characteristic response kinetics frequently showing delayed activity, but resulting in durable remission in a considerable proportion of the responding patients. On the other hand, antitumor activity is frequently accompanied by significant toxicity. The spectrum of side effects is different from that of conventional therapies, and a large part of them is caused by the enhanced systemic immune activity. In order to spare non-responding patients of the severe side effects and to increase response rate, the search for biomarkers that could help in identifying patients likely to react to the treatment represents an important focus of studies. Furthermore, development of combinations with other immunotherapeutic modalities, chemo- or targeted therapies may further increase the efficiency of immunomodulatory antibodies.