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O papel dos inibidores de checkpoint na terapêutica oncológica: situação atual e perspectivas para o futuro
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O avanço na Ciência e investigação na área do Cancro, uma doença capaz de causar elevadas taxas de morbilidade e mortalidade, permitiu determinar o papel do sistema imunitário no combate neoplásico, potenciando a sua resposta antitumoral com recurso às várias estratégias do âmbito da imunoterapia. Os inibidores dos checkpoints imunitários incluem-se nesta classe e apresentam-se como medicamentos dirigidos aos recetores da superfície celular cujo balanço entre sinais coestimuladores e coinibidores medeia a resposta imune em vários contextos, nomeadamente o tumoral; tendo como alvos principais as vias CTLA-4 e PD-1/PD-L1, estes fármacos são, assim, capazes de modular a atividade antineoplásica imunitária, favorecendo-a através de efeitos como a promoção da ativação linfocitária e reversão da exaustão celular T.
Encontram-se atualmente aprovados em Portugal seis fármacos dirigidos ao recetor PD-1 e ligando PD-L1 – Atezolizumab, Avelumab, Cemiplimab, Durvalumab, Nivolumab e Pembrolizumab – e o Ipilimumab, inibidor do CTLA-4; estes têm indicação em várias neoplasias em monoterapia ou combinação com outros agentes farmacológicos, como melanoma, cancro do pulmão, carcinoma das células renais, urotelial, colorretal, das células de Merkel, das células escamosas da cabeça e pescoço, Linfoma de Hodgkin, entre outras. A sua utilização tem demonstrado outcomes clínicos favoráveis, com duração de resposta mais prolongada, aumento da sobrevivência global e livre de progressão associadas a toxicidade aceitável; em parte deve-se ao uso de biomarcadores, que determinam previamente que doentes beneficiarão desta terapêutica e monitorizam a sua eficácia.
Ainda assim, o número de doentes com resultados positivos é reduzido, não só pelo desenvolvimento de resistências, mas também pelo aparecimento de reações adversas, ainda que mais toleráveis que as associadas à terapêutica convencional; mediadas pelo sistema imunitário, podem ser controladas com imunomoduladores, ou suspensão e descontinuação da administração dos inibidores dos checkpoints imunitários em casos mais graves.
O futuro destes fármacos é promissor, e passa pela otimização da utilização dos medicamentos já aprovados, aplicando o seu mecanismo de ação a outras indicações e combinando com várias abordagens terapêuticas, pela aprovação de fármacos dirigidos aos diferentes checkpoints imunitários e pela investigação de diferentes biomarcadores e modelos pré-clínicos.
The advances in Science and research in the area of Cancer, a disease responsible for high rates of morbidity and mortality, have made it possible to determine the role of the immune system in fighting cancer, enhancing its antitumor response with various strategies in the field of immunotherapy. Immune checkpoints inhibitors are included in this class and are presented as medicines directed to cell surface’s receptors whose balance between the co-stimulator and co-inhibitor signals mediates the immune response in various contexts, namely the tumor; having as main targets the CTLA-4 and PD-1/PD-L1 pathways, these drugs are thus capable of modulating the immune antitumor activity, favoring it through effects such as the promotion of lymphocytic activation and reversal of cell exhaustion T. Six drugs targeting the PD-1 receptor and PD-L1 ligand - Atezolizumab, Avelumab, Cemiplimab, Durvalumab, Nivolumab and Pembrolizumab – and Ipilimumab, a CTLA-4 inhibitor, are currently approved in Portugal; these are indicated in various neoplasms alone or combined with other pharmacological agents, such as melanoma, lung cancer, renal cell, urothelial, colorectal, Merkel cells and head and neck squamous cell carcinomas, Hodgkin's lymphoma, among others. Its use has demonstrated favorable clinical outcomes, with longer response duration, increased overall and progression-free survival associated with acceptable toxicity, partly due to the use of biomarkers, which determine in advance which patients will benefit from this therapy and monitor its efficacy. Nevertheless, the number of patients with positive results is reduced, not only because of the development of resistance, but also because of the appearance of side effects, although more tolerable than those associated with conventional therapy; mediated by the immune system, can be controlled with immunomodulators, or with suspension and/or discontinuation of immune checkpoint inhibitors’s administration in more severe cases. The future of these drugs is promising, and involves optimizing the use of already approved drugs, applying their mechanism of action to other indications, and combining them with other various therapeutic approaches, approving drugs directed to different immune checkpoints and investigating different biomarkers and pre-clinical models.
The advances in Science and research in the area of Cancer, a disease responsible for high rates of morbidity and mortality, have made it possible to determine the role of the immune system in fighting cancer, enhancing its antitumor response with various strategies in the field of immunotherapy. Immune checkpoints inhibitors are included in this class and are presented as medicines directed to cell surface’s receptors whose balance between the co-stimulator and co-inhibitor signals mediates the immune response in various contexts, namely the tumor; having as main targets the CTLA-4 and PD-1/PD-L1 pathways, these drugs are thus capable of modulating the immune antitumor activity, favoring it through effects such as the promotion of lymphocytic activation and reversal of cell exhaustion T. Six drugs targeting the PD-1 receptor and PD-L1 ligand - Atezolizumab, Avelumab, Cemiplimab, Durvalumab, Nivolumab and Pembrolizumab – and Ipilimumab, a CTLA-4 inhibitor, are currently approved in Portugal; these are indicated in various neoplasms alone or combined with other pharmacological agents, such as melanoma, lung cancer, renal cell, urothelial, colorectal, Merkel cells and head and neck squamous cell carcinomas, Hodgkin's lymphoma, among others. Its use has demonstrated favorable clinical outcomes, with longer response duration, increased overall and progression-free survival associated with acceptable toxicity, partly due to the use of biomarkers, which determine in advance which patients will benefit from this therapy and monitor its efficacy. Nevertheless, the number of patients with positive results is reduced, not only because of the development of resistance, but also because of the appearance of side effects, although more tolerable than those associated with conventional therapy; mediated by the immune system, can be controlled with immunomodulators, or with suspension and/or discontinuation of immune checkpoint inhibitors’s administration in more severe cases. The future of these drugs is promising, and involves optimizing the use of already approved drugs, applying their mechanism of action to other indications, and combining them with other various therapeutic approaches, approving drugs directed to different immune checkpoints and investigating different biomarkers and pre-clinical models.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2021, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Imunoterapia Checkpoints imunitários Inibidores dos checkpoints imunitários Anti-PD-1 Anti-CTLA-4 Mestrado integrado - 2021