RESUMO
Background: Cancers escape immune surveillance via distinct mechanisms that involve central (negative selection within the thymus) or peripheral (lack of costimulation, receipt of death/anergic signals by tumor, immunoregulatory cell populations) immune tolerance. During the 1990s, moderate clinical benefit was seen using several cytokine therapies for a limited number of cancers. Over the past 20 years, extensive research has been performed to understand the role of various components of peripheral immune tolerance, with the co-inhibitory immune checkpoint molecules cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand (PD-L1) being the most well-characterized at preclinical and clinical levels. Patients and methods: We used PubMed and Google Scholar searches to identify key articles published reporting preclinical and clinical studies investigating CTLA-4 and PD-1/PD-L1, frequently cited review articles, and clinical studies of CTLA-4 and PD-1/PD-L1 pathway inhibitors, including combination therapy strategies. We also searched recent oncology congress presentations and clinicaltrials.gov to cover the most up-to-date clinical trial data and ongoing clinical trials of immune checkpoint inhibitor (ICI) combinations. Results: Inhibiting CTLA-4 and PD-1 using monoclonal antibody therapies administered as single agents has been associated with clinical benefit in distinct patient subgroups across several malignancies. Concurrent blockade of CTLA-4 and components of the PD-1/PD-L1 system using various schedules has shown synergy and even higher incidence of durable antitumor responses at the expense of increased rates of immune-mediated adverse events, which can be life-threatening, but are rarely fatal and are reversible in most cases using established treatment guidelines. Conclusions: Dual immune checkpoint blockade has demonstrated promising clinical benefit in numerous solid tumor types. This example of concurrent modulation of multiple components of the immune system is currently being investigated in other cancers using various immunomodulatory strategies.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antineoplásicos Imunológicos/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Humanos , Seleção de Pacientes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Evasão TumoralRESUMO
Although patients diagnosed with melanoma of = 1.00 mm thickness have a relatively good cure rate, the prognosis for patients with locally advanced and metastatic melanoma is grave. The discovery of new and effective therapies for this disease depends in large part on molecular studies that will resolve why advanced-stage melanoma is refractory to conventional chemotherapy and radiation therapy. To identify genes that have important functions in advanced-stage melanomas, in particular, in melanoma-infiltrated lymph nodes, which are not well characterized at the molecular level, we generated a LongSAGE library from a melanoma-positive lymph node, and subjected melanoma-infiltrated lymph nodes to protein expression profiling. The data document that the molecular signature of melanoma, which has spread to regional lymph nodes, is very similar to the molecular signature of primary melanomas. Equally important, we provide evidence that the ubiquitin-conjugating enzyme, Ubc9, is expressed at high levels in melanoma-positive lymph nodes, and that it plays a crucial role in preventing advanced-stage melanomas from undergoing chemotherapy-induced apoptosis.