Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.336
Filtrar
2.
Medicine (Baltimore) ; 99(24): e20545, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541476

RESUMO

Anti-programmed death-1 (PD-1) therapy has been extensively used to treat cancer. Recently, the combination of immunotherapy and anti-angiogenic therapy has emerged as a novel treatment approach. Therefore, we designed a study to evaluate the real-world benefit of the combination of anti-PD-1 and anti-angiogenesis therapy in patients with non-small cell lung cancer (NSCLC).We obtained the medical records of patients at the Chinese People's Liberation Army General Hospital who received either nivolumab or pembrolizumab combined with anti-angiogenesis therapy from January 2015 to December 2018. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated for all patients.Sixty-nine patients with NSCLC were included in our study. The ORR was 31.9% (95% CI: 20.6-43.2%) and the median PFS was 8.37 months (95% CI: 6.5-10.0 months). The subgroup analysis statistically revealed a significant difference in ORR for patients receiving first-line treatment vs other lines, and the values were 58.8% (95% CI: 32.7-84.9%) compared with 23.1% (95% CI: 11.2-34.9%). We also observed a significant improvement in PFS, with a median value of 10.5 months (95% CI: 7.4-13.1 months) for patients without EGFR mutations and 5.4 months (95% CI: 4.0-6.3 months) for patients with EGFR mutations.The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients' different baseline characteristics. Importantly, compared with patients having identified EGFR mutations, patients without EGFR mutations had a better PFS. Furthermore, these data support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
Sheng Wu Gong Cheng Xue Bao ; 36(5): 969-978, 2020 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-32567280

RESUMO

Drugs targeting immune checkpoint are used for cancer treatment, but resistance to single drug may occur. Combination therapy blocking multiple checkpoints simultaneously can improve clinical outcome. Therefore, we designed a recombinant protein rPC to block multiple targets, which consists of extracellular domains of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The coding sequence was inserted into expression vector and stably transfected into HEK293 cells. The culture supernatant was collected and rPC was affinity-purified. Real-time quantitative PCR was used to evaluate the expression levels of ligands for PD-1 and CTLA-4 in several human cancer cell lines. The binding of rPC with cancer cells was examined by immunofluorescence cell staining, the influence of rPC on cancer cell growth was assayed by CCK-8. The results showed that rPC could be expressed and secreted by stably transfected HEK293 cells, the purified rPC could bind to lung cancer NCI-H226 cells which have high levels of ligands for PD-1 and CTLA-4, no direct impact on cancer cell growth could be observed by rPC treatment. The recombinant protein rPC can be functionally assayed further for developing novel immunotherapeutic drugs for cancer.


Assuntos
Neoplasias Pulmonares , Proteínas Recombinantes de Fusão , Animais , Antígeno CTLA-4/genética , Proliferação de Células , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Domínios Proteicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/isolamento & purificação , Proteínas Recombinantes de Fusão/metabolismo
5.
Anticancer Res ; 40(5): 2707-2713, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366416

RESUMO

BACKGROUND/AIM: Using a syngeneic tongue cancer mouse model, the effect of CD40 agonist and PD-1 antagonist combination therapy for local recurrence after surgery was evaluated in a partially depleted CD4 model. MATERIALS AND METHODS: C3H/HeN mice were injected with 0.05 mg of the anti-mouse CD4 clone GK1.5, causing partial depletion of CD4 cells. Tongue cancer was induced by injecting the squamous cell carcinoma (SCC) VII cell line, the tumor was resected by partial glossectomy, and CD40 agonist and/or PD-1 antagonist therapy was administered postoperatively. RESULTS: Partial depletion of CD4 cells resulted in faster growth of a recurring tumor in the tongue, faster loss of body weight, and decreased number of CD8a-positive cells in the tumor. Postoperative adjuvant therapy with a combination of CD40 agonist and PD-1 antagonist resulted in a significant increase in survival compared to the CD40 agonist single treatment. CONCLUSION: CD40 agonist and PD-1 antagonist combination therapy could be an effective postoperative adjuvant treatment, especially in cases with decreased CD4 T cell activity.


Assuntos
Antígenos CD40/agonistas , Cuidados Pós-Operatórios , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Língua/terapia , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Recidiva Local de Neoplasia/patologia , Neoplasias da Língua/patologia , Neoplasias da Língua/cirurgia
6.
N Engl J Med ; 382(20): 1894-1905, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32402160

RESUMO

BACKGROUND: The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. METHODS: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). RESULTS: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. CONCLUSIONS: In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Análise de Sobrevida
7.
Crit Rev Oncol Hematol ; 151: 102965, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32442903

RESUMO

Glioblastoma (GBM) is the most common malignant tumour in the brain, and current treatments are not curative and cannot control recurrence. This limitation indirectly places immunotherapy at the focus of translational GBM research. Many studies on the PD-1/PD-L1 axis in GBM are ongoing, and the immunosuppressive mechanism of PD-1/PD-L1 in GBM is different from that in other solid tumours. This review focuses on the effect of the PD-1/PD-L1 axis on infiltrating immune cells in the suppressive GBM immune microenvironment and summarizes the recent progress in PD-1/PD-L1 axis-related therapies reported in preclinical and clinical GBM studies, providing a reference for the systematic study of PD-1/PD-L1 axis-related anti-GBM immunity.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral
9.
Am Surg ; 86(4): 284-292, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32391751

RESUMO

Progress in the arena of cancer immunotherapy has been immense in recent years. The fact remains that most of the cancer resections in the United States are performed by general surgeons and not oncologic specialists. A busy practice in general surgery will invariably make it difficult to keep pace with such rapid advancement. This review offers a concise summary of the major concepts and trials that have driven the immunotherapy revolution and their implications for surgeons who deliver cancer care.


Assuntos
Imunoterapia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Imunoterapia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia
11.
Cancer Treat Rev ; 87: 102031, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446182

RESUMO

Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) quickly subverted the standard of treatment in Non-Small Cell Lung Cancer (NSCLC), where they were first introduced in all comers previously treated advanced/metastatic NSCLC patients and subsequently in the first line of PD-L1 selected cases of metastatic and locally advanced disease. Treatment algorithm is an evolving landscape, where the introduction of front-line ICIs, with or without chemotherapy, unavoidably influences the following treatment lines. In this context, medical oncologists are currently facing many unclear issues, which have been not clarified so far by available data. Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients - are only a part of the unexplored side of ICIs in the real world. Indeed, pivotal randomized clinical trials (RCTs) often lack of external validity because eligibility criteria exclude some patient subgroups commonly treated in real-world clinical practice. Similarly, cost-effectiveness and sustainability of these innovative agents are important issues to be considered in the real-world. Though affected by several limitations, real-world evidence (RWE) studies allow to collect data regarding overall treated patients in clinical practice according to local authority regulations, overcoming the intrinsic limits of RCTs. The present review focuses on RWE about ICIs in lung cancer treatment, with particular reference to special patient populations, and discusses potential application of real-world data in a potential innovative drug development model.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
J Immunother Cancer ; 8(1)2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32434790

RESUMO

COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Infecções por Coronavirus/diagnóstico , Neoplasias/terapia , Pneumonia Viral/diagnóstico , Antineoplásicos Imunológicos/efeitos adversos , Humanos , Terapia de Alvo Molecular , Pandemias , Receptor de Morte Celular Programada 1/antagonistas & inibidores
13.
Anticancer Res ; 40(4): 2247-2255, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234921

RESUMO

BACKGROUND/AIM: The efficacy of treatment using the anti-programmed cell death-1 (anti-PD-1) antibody for metastatic gastric cancer (mGC) has been established previously. Exploratory analyses in various types of tumours suggest that prior exposure to immune checkpoint inhibitors can enhance the efficacy of subsequent cytotoxic chemotherapy (CTx). Our aim is to evaluate the efficacy and safety of CTx for mGC after progression on anti-PD-(ligand) 1 [anti-PD-(L)1] antibody. PATIENTS AND METHODS: We retrospectively evaluated patients with mGC who underwent CTx. The patients received CTx after progression on anti-PD-(L)1 antibody (cohort A) or as a third-line treatment without prior exposure to anti-PD-(L)1 antibody (cohort B). We evaluated: i) clinical characteristics, ii) efficacies, iii) prognoses, and iv) adverse events (AEs). RESULTS: In cohorts A and B, 16 and 68 patients fulfilled the criteria, respectively. In the univariate analysis, the overall response rate was significantly higher in cohort A compared to cohort B (31% vs. 10%, respectively; Odds Ratio:3.96, 95% Confidence Interval:1.06-14.8, p=0.040). The multivariate analysis showed a similar trend. Immune-related AEs did not worsen and were manageable, while new immune-related AEs were not observed. CONCLUSION: CTx after progression on anti-PD-(L)1 antibody demonstrated a favourable efficacy in intensively treated patients with mGC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/metabolismo , Citotoxinas/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Resultado do Tratamento
14.
BMJ ; 369: m736, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32253223

RESUMO

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.


Assuntos
Imunoterapia/métodos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos , Antineoplásicos Imunológicos , Antígeno CTLA-4 , Humanos , Fatores Imunológicos , Imunoterapia/efeitos adversos , Imunoterapia/estatística & dados numéricos , Ipilimumab , Neoplasias/terapia , Receptor de Morte Celular Programada 1 , Microambiente Tumoral
15.
APMIS ; 128(2): 177-187, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32304591

RESUMO

Exhausted and dysfunctional T cells triggered by infection and cancer render the immune system unable to eliminate these pathogens. Pharmacologic blockade of the surface receptors that inhibit T-cell function has shown remarkable success in patients with various malignancies. In this Review, we discuss the emerging evidence of inhibiting checkpoint pathways as a potential role in controlling or clearing infectious diseases. Though interesting tendencies, much work is still needed in order to develop safe strategies that can be translated into clinically relevant outcomes in patients with infections.


Assuntos
Doenças Transmissíveis/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Linfócitos T/metabolismo
16.
Int J Clin Oncol ; 25(5): 801-809, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32246277

RESUMO

Significant technological advances in radiotherapy have been made in the past few decades. High-precision radiotherapy has recently become popular and is contributing to improvements in the local control of the irradiated target lesions and the reduction of adverse effects. Accordingly, for long-term survival, the importance of systemic cancer control, including at non-irradiated sites, is growing. Toward this challenge, the treatment methods in which anti-PD-1/PD-L1 antibodies that exert systemic effects by restoring anti-tumour immunity are combined with radiotherapy has attracted attention in recent years. Previous studies have reported the activation of anti-tumour immunity by radiotherapy, which simultaneously elevates PD-L1 expression, suggesting a potential for combination therapy. Radiotherapy induces so-called 'immunogenic cell death', which involves cell surface translocation of calreticulin and extracellular release of high-mobility group protein box 1 (HMGB-1) and adenosine-5'-triphosphate (ATP). Furthermore, radiotherapy causes immune activation via MHC class I upregulation and cGAS-STING pathway. In contrast, induction of immunosuppressive lymphocytes and the release of immunosuppressive cytokines and chemokines by radiotherapy contribute to immunosuppressive reactions. In this article, we review immune responses induced by radiotherapy as well as previous reports to support the rationale of combination of radiotherapy and anti-PD-1/PD-L1 antibodies. A number of preclinical and clinical studies have shown the efficacy of radiotherapy combined with immune checkpoint inhibition, hence combination therapy is considered to be an important future strategy for cancer treatment.


Assuntos
Antígeno B7-H1/imunologia , Terapia Combinada/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Animais , Anticorpos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Humanos , Imunossupressão/métodos , Imunoterapia/métodos , Neoplasias/radioterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Pesquisa Médica Translacional , Resultado do Tratamento
17.
Adv Exp Med Biol ; 1244: 93-106, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301012

RESUMO

Gastrointestinal (GI) cancers represent a variety of malignancies, each with a unique interplay between the tumor and local immune microenvironment. The successes that immunotherapy, particularly immune checkpoint inhibition, has brought to various other solid tumors have largely not yielded the same benefits to patients with GI cancers. There are subsets of patients for whom immunotherapy has been FDA approved in recent years. For example, anti-PD-1 therapy is approved for patients with pretreated hepatocellular carcinoma. Additionally, patients with PD-L1-positive gastric cancer are eligible to receive anti-PD-1 therapy in the third line setting. Outside of the rare subset of patients who harbor MSI-H/dMMR tumors, the vast majority of patients with colorectal, anal, biliary tract, and pancreatic cancers have not responded to single-agent immune checkpoint inhibitors. Innovative techniques with thoughtful treatment combinations, adoptive cell therapy, CAR-T cells, as well as novel predictive biomarkers are needed to bring the benefits of immunotherapy to the majority of patients with GI malignancies.


Assuntos
Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Imunoterapia , Humanos , Imunoterapia Adotiva , Receptor de Morte Celular Programada 1/antagonistas & inibidores
18.
Adv Exp Med Biol ; 1244: 107-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301013

RESUMO

The past decade has witnessed a revolution of immune checkpoint inhibitors in the treatment of multiple tumor types, including genitourinary cancers. Immune checkpoint inhibitors improved the treatment outcomes of patients with metastatic renal cell carcinoma and metastatic urothelial carcinoma. In prostate cancer, the role of immunotherapy with checkpoint inhibitors is not yet established, but clinical trials investigating their use are ongoing. Other immunotherapeutic approaches that have been explored in these malignancies include cytokines, vaccines, and cellular therapy. Ongoing studies are exploring the use of immunotherapy combinations as well as combination with chemotherapy and targeted therapy in these types of tumors. The use of immunotherapy beyond the metastatic setting is an active area of research. Moreover, there is a great interest in biomarker development to predict response to immunotherapy and risk of toxicity. This chapter is a comprehensive review of the immunotherapeutic approaches, both approved and investigational, for the treatment of renal cell carcinoma, urothelial carcinoma, and prostate cancer.


Assuntos
Imunoterapia , Neoplasias Urogenitais/terapia , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Urogenitais/imunologia
19.
Nature ; 580(7804): 517-523, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32322066

RESUMO

A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Mutação , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/imunologia , Reparo de Erro de Pareamento de DNA/genética , Frequência do Gene , Genoma Humano/efeitos dos fármacos , Genoma Humano/genética , Glioma/imunologia , Humanos , Masculino , Camundongos , Repetições de Microssatélites/efeitos dos fármacos , Repetições de Microssatélites/genética , Mutagênese/efeitos dos fármacos , Mutação/efeitos dos fármacos , Fenótipo , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sequência de DNA , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
20.
PLoS One ; 15(4): e0231003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240238

RESUMO

Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Imunoterapia/métodos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA