|
|
| [PMID]: | 28335888 |
| [Au] Autor: | Dempke WCM; Fenchel K; Uciechowski P; Dale SP |
| [Ad] Endereço: | Kyowa Kirin Pharmaceutical Development, Galashiels, United Kingdom; University of Munich, University Hospital of Grosshadern, Department of Haematology and Oncology, Germany. Electronic address: wolfram.dempke@kyowakirin.com. |
| [Ti] Título: | Second- and third-generation drugs for immuno-oncology treatment-The more the better? |
| [So] Source: | Eur J Cancer;74:55-72, 2017 Mar. | | [Is] ISSN: | 1879-0852 |
| [Cp] País de publicação: | England |
| [La] Idioma: | eng |
| [Ab] Resumo: | Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and ß-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field. |
| [Mh] Termos MeSH primário: |
Anticorpos Monoclonais Humanizados/uso terapêutico
Antineoplásicos/uso terapêutico
Imunoterapia/métodos
Neoplasias/terapia
|
| [Mh] Termos MeSH secundário: |
Antígenos CD/efeitos dos fármacos
Linfócitos B/imunologia
Antígenos B7/antagonistas & inibidores
Antígenos B7/imunologia
Antígenos CD40/agonistas
Antígeno CTLA-4/antagonistas & inibidores
Citocinas/imunologia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/efeitos dos fármacos
Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores
Seres Humanos
Imunidade Celular/fisiologia
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores
Proteína Coestimuladora de Linfócitos T Induzíveis/agonistas
Células Matadoras Naturais/imunologia
Ativação Linfocitária/imunologia
Complexo Principal de Histocompatibilidade/imunologia
Neoplasias/imunologia
Ligante OX40/agonistas
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Receptores KIR/antagonistas & inibidores
Subpopulações de Linfócitos T/imunologia
Linfócitos T Citotóxicos/imunologia
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE; REVIEW |
[Nm] Nome de substância:
| 0 (Antibodies, Monoclonal, Humanized); 0 (Antigens, CD); 0 (Antineoplastic Agents); 0 (B7 Antigens); 0 (CD223 antigen); 0 (CD40 Antigens); 0 (CTLA-4 Antigen); 0 (Cytokines); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (OX40 Ligand); 0 (Programmed Cell Death 1 Receptor); 0 (Receptors, KIR); 0 (TNFRSF18 protein, human); 0 (TNFRSF9 protein, human); 0 (TNFSF4 protein, human); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9); 0 (VISTA protein, human) |
| [Em] Mês de entrada: | 1708 |
| [Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 170325 |
| [St] Status: | MEDLINE |
| |
|
|
