Revisão e Atualização dos Inibidores dos Checkpoints Immunológicos no Melanoma

Eugénia Matos Pires, Cecília Moura

Resumo


A incidência do melanoma está a aumentar de uma forma global e essa tendência manter-se-á muito provavelmente nas próximas duas décadas. Estes dados reforçam a necessidade de novos alvos terapêuticos, em alternativa à quimioterapia clássica para o tratamento do melanoma avançado. Com efeito, ao longo da última década, os novos conhecimentos relativos à biologia tumoral revolucionaram a terapêutica do melanoma, incluindo a imunoterapia com os inibidores dos “checkpoints” imunológicos, cujos alvos terapêuticos são as proteínas CTLA-4 (cytotoxic T lymphocyte-associated protein 4) e PD-1 (programmed cell death protein 1). A inibição destes alvos permite a modulação da resposta imune do hospedeiro contra o desenvolvimento tumoral, com respostas objetivas sustentadas no controlo da doença. Face a estes resultados, a imunoterapia tornou-se o tratamento de referência nos doentes com melanoma avançado (estadio III irressecável ou estadio IV, com metástases à distância), sem mutação BRAF identificada. O ipilimumab (anti CTLA-4) foi o primeiro “checkpoint” imunológico inibitório a demonstrar aumento na sobrevida global no tratamento do melanoma avançado. Mais tarde, o nivolumab e o pembrolizumab (ambos anti-PD-1) evidenciaram melhores resultados em termos de sobrevida global e tolerabilidade do que o ipilimumab. Estes resultados são expectáveis, na medida em que as vias de inibição dos “checkpoints” imunológicos são diferentes. Neste contexto, impõe-se a avaliação da eficácia da terapêutica combinada e a identificação de biomarcadores que possibilitem a previsão de resposta aos anti-CTLA-4 e anti-PD-1. Após um trabalho prévio em que foram sumariamente revistos os mecanismos de desenvolvimento tumoral e de ação dos “checkpoints” imunológicos inibitórios, propomo-nos efetuar uma revisão sobre os inibidores dos “checkpoints” imunológicos, atualmente disponíveis na prática clínica para o tratamento do melanoma avançado.


Palavras-chave


Anticorpos Monoclonais; Antígeno CTLA-4; Imunoterapia; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab; Pontos de Controlo do Ciclo Celular; Receptor de Morte Celular Programada 1

Texto Completo:

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DOI: http://dx.doi.org/10.29021/spdv.76.3.970

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