Immune Checkpoint Inhibitors in Melanoma: Review and Update

Abstract

The overall increasing incidence of melanoma will very probably be the trend over the next two decades. This data stresses the need for new therapeutic resources, other than classic chemotherapy. Nevertheless, the treatment of advanced melanoma has been changed in the last decade due to novel therapeutic strategies, including immunotherapy with immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Inhibition of these targets enhances immune host response against cancer and results in durable objective responses, establishing immunotherapy as standard treatment for BRAF wild-type melanoma patients in advanced stages (III – unresectable and IV – metastases at distant sites). Anti-CTLA-4, ipilimumab, was the first–in-class immune checkpoint inhibitor to show improvement in overall survival in advanced melanoma. Latter, anti-PD-1 agents, nivolumab and pembrolizumab, have improved tumour response and tolerability in comparison with ipilimumab. Differences in outcome are expected considering the distinct target of checkpoint inhibition pathways. In this setting, it is of utmost importance the assessment of efficacy by combined therapy and the identification of biomarkers capable of predicting response to anti-CTLA-4 and anti-PD-1. After a previous review on cancer biology and mechanisms of action of immune checkpoint inhibitors we will focus on the main data on the immune checkpoint inhibitors for melanoma currently available in daily practice.

Terapêutica Sistémica no Melanoma Avançado Systemic Therapy in Advanced Melanoma

“…A nova classe de imunomodeladores ultrapassa a resposta inata e tem como alvo a activação de receptores dos linfócitos T, receptores esses que são co-estimuladores (Ex: OX40 (CD134), GITR (glucocorticoid-induced TNF receptor related gene) ou o bloqueio de receptores co--inibidores (ex: CTLA-4, PD-1 e PD-L1), 3,4 moléculas que são discutidas no artigo. 5 Com a experiência clínica adquirida e com os avanços na compreensão dos mecanismos de oncogénese e progressão tumoral novas vias de tratamento estão a ser investigadas, como outras moléculas com importância no equilíbrio imunitário e/ou microambiente tumoral, por exemplo outros receptores co-inibidores como anti-LAG-3 (lymphocyte-activation gene 3), TIM-3 (T cell immunoglobulin-3), VISTA (V-domain Ig suppressor of T cell activation) , TIGIT (T cell immunoglobulin and ITIM domain), anti -GITR (glucocorticoid induced TNF receptor), inibidores IDO1 (inhibitors of indoleamine 2,3-dioxygenase-1), inibidores HDAC (histone deacetylase inhibitors), anticorpos bloqueadores CD73, antagonistas do receptor da adenosina 2A, ou reformulação de "velhas moléculas" como a interleucina, que surge agora sob a designação de NEKTAR-214 (citoquina peguilada, CD122-biased agonist), recuperando a sua eficácia principalmente em associação com moléculas anti-PDL-1. São, pois, inúmeras moléculas novas que tentam provar o seu valor isoladamente ou em combinações, melhorando a resposta imunitária contra as células tumorais em geral, e do melanoma em particular.…”