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The Era of Checkpoint Inhibition: Lessons Learned from Melanoma.
Recent Results Cancer Res ; 214: 169-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473853
ABSTRACT
Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8+ T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8+ T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Linfócitos T CD8-Positivos / Receptor de Morte Celular Programada 1 / Imunoterapia / Melanoma Aspecto clínico: Predição / Prognóstico Limite: Humanos País/Região como assunto: Europa Idioma: Inglês Revista: Recent Results Cancer Res Ano de publicação: 2020 Tipo de documento: Artigo País de afiliação: Alemanha