Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 14.935
Filtrar
1.
Medicine (Baltimore) ; 98(36): e16873, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31490371

RESUMO

At present, intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is recommended for prophylaxis purposes after transurethral resection of bladder tumor, but has chances of recurrence. Radical cystectomy reduces the risk of recurrence in bladder cancer patients, but may have chances of postoperative complications. The objective of the study was to test the hypothesis that radical cystectomy has overtreatment and definitive BCG immunotherapy has undertreatment in intermediate or high-risk nonmuscle invasive bladder cancer patients. Data regarding biopsies, ultrasound, the computed tomography scan, adopted treatment strategy, treatment-emergent adverse effect, and a follow-up period of 312 patients with confirmed nonmuscle invasive bladder cancer (pTa, pTis, or pT1 stage; intermediate or high-risk cancer) were reviewed. Patients who had received definitive intravesical BCG immunotherapy were included in BCG group (n = 210) and those who underwent radical cystectomy were included in RXC group (n = 87). Clinical decision-making for treatment strategies was evaluated for both groups. Cystitis was frequently observed in all patients who received BCG immunotherapy. In RXC group, ileus was frequently observed in all patients in early days after the operation. During 2 years of the follow-up period, biopsies, ultrasound, and the computed tomography scan reported that BCG group had fewer numbers of negative cancer patients after treatment than the RXC group after surgery (P < .0001). Total expenditure for BCG immunotherapy was higher than radical cystectomy (22,945 ±â€Š945 ¥/patient vs 17,985 ±â€Š545 ¥/patient; P < .0001). Definitive BCG immunotherapy had undertreatment and radical cystectomy had overtreatment for intermediate or high-risk invasive bladder cancer patients (level of evidence III).


Assuntos
Vacina BCG/uso terapêutico , Cistectomia/estatística & dados numéricos , Imunoterapia/métodos , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Adolescente , Adulto , Idoso , Vacina BCG/efeitos adversos , Vacina BCG/economia , Análise Custo-Benefício , Cistectomia/efeitos adversos , Cistectomia/economia , Feminino , Comportamentos Relacionados com a Saúde , Humanos , Imunoterapia/economia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores Socioeconômicos , Neoplasias da Bexiga Urinária/patologia , Adulto Jovem
2.
Zhonghua Wai Ke Za Zhi ; 57(10): 77-82, 2019 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-31510736

RESUMO

Programmed cell death protein 1 (PD-1/CD279) and cytotoxic T Lymphocyte Antigen-4 (CTLA-4) are important immune checkpoints, through the role of the corresponding ligands and inhibit T cell activation and production of cytokines, in maintaining the body's vital role in peripheral tolerance. The use of anti-CTLA-4/PD-1 /PD-L1 monoclonal antibodies to block the tumor signaling pathway has shown excellent anti-tumor efficacy in a variety of solid tumors, and it is expected that immunotherapy will be available for the treatment of 60% advanced tumors in the next decade. Esophageal cancer is one of the major causes of cancer-related deaths worldwide, and its 5-year survival rate is generally low. Currently, radiotherapy, chemotherapy, and surgery are the standard treatments for esophageal cancer, and there is no effective treatment scheme for patients with esophageal cancer who fail to respond to standard treatment. Due to the diversity of somatic cell gene mutations and the generation of neo-antigens in esophageal cancer, immunotherapy has become a feasible treatment scheme to improve the prognosis of esophageal cancer. In this situation, the application of immunotherapy for esophageal cancer or more specific immune checkpoint inhibitors has gradually become the focus of the treatment of esophageal cancer. Nowadays, the research of immune checkpoint inhibitors, such as ipilimumab, tremelimumab, pembrolizumab, nivolumab and avelumab on esophageal cancer is proceeding at an amazing speed. The phase Ⅰ b clinical study of immunotherapy for esophageal cancer, which previously attracted great interest, has been replaced by the phase Ⅲ clinical study, and the results of the relevant studies also show a good prospect for the application of immune checkpoint inhibitors for esophageal cancer. However, the prediction of therapeutic effect and the selection of the best candidates still need to be further studied.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Esofágicas/imunologia , Humanos , Imunoterapia/métodos , Prognóstico
3.
Cancer Immunol Immunother ; 68(9): 1493-1500, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31501955

RESUMO

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.


Assuntos
Imunoterapia/métodos , Melanoma/metabolismo , Ligante OX40/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Ligante OX40/genética , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Sobrevida , Resultado do Tratamento
4.
Cancer Immunol Immunother ; 68(9): 1527-1535, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31535160

RESUMO

BACKGROUND: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/terapia , Imunoterapia/métodos , Idoso , Neoplasias do Sistema Biliar/mortalidade , China , Terapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
5.
Magy Onkol ; 63(3): 239-245, 2019 09 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31538441

RESUMO

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.


Assuntos
Imunoterapia/mortalidade , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Hungria , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Prognóstico , Medição de Risco , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
6.
Cancer Treat Rev ; 79: 101887, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491661

RESUMO

Small cell lung cancer (SCLC) was defined as a "recalcitrant cancer" because of its dismal prognosis and lack of outcome improvements in the last 30 years. Immunotherapy with checkpoint inhibitors revolutionized treatment in many cancer types and results from the IMpower133 study, a double-blind placebo-controlled phase III trial, showed overall survival benefit for atezolizumab when added to standard platinum-etoposide chemotherapy in first-line SCLC setting for the first time since years. Trials with other checkpoint inhibitors, e.g. pembrolizumab, durvalumab, nivolumab and ipilimumab, are ongoing in various settings, but, to date, there are no defined factors to identify patients who are more likely to benefit from such treatments. This review summarizes results of immunotherapy trials in SCLC for first-line, maintenance and further-line therapies for single-agents and combinations with checkpoint inhibitors. Predictive factors from these trials are reviewed in order to identify their clinical value, with particular emphasis on PD-L1 expression on both tumor cells and in stroma, especially in pembrolizumab-treated patients, and tumor mutational burden, for patients treated with the ipilimumab and nivolumab combination.


Assuntos
Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
7.
Zhonghua Zhong Liu Za Zhi ; 41(9): 641-647, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550852

RESUMO

Over the past decades, although the clinical efficacy of advanced head and neck squamous cell carcinoma (HNSCC) has been moderately improved by the combination of cetuximab and chemotherapy, no remarkable treatment has emerged. The prognosis of HNSCC is still unsatisfied. With the deeper exploration of tumor immunological therapy, immunocheckpoint inhibitors such as monoclonal antibodies targeting on programmed cell death protein 1 (PD-1)/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have shown appreciable anti-tumor effect on cancers such as melanoma and non-small cell lung cancer. Some successful clinical studies on HNSCC have also been reported, which provide a new opportunity for the improvement of HNSCC prognosis.Here we systemically review the progress of checkpoint inhibitors and its combination therapy in HNSCC, some immunotherapy efficacy-related biomarkers are also discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
8.
Ther Umsch ; 76(4): 187-194, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498037

RESUMO

Immunotherapies - Overview, mode of action and clinical implications Abstract. The introduction of immunotherapies has led to major advances in the treatment of cancer patients. The mainstays of immunotherapies in clinical routine are immune checkpoint inhibitors. Immune checkpoints like CTLA-4 or the PD-1 / PD-L1 axis are important contributors to the immune homeostasis by preventing overshooting immune responses against pathogens and thus preventing collateral damage to normal tissue, or by preventing autoimmunity. However, immune checkpoints can impede the development of an efficient anti-tumor immune response. Thus, therapeutic monoclonal antibodies against CTLA-4 and PD-1 or PD-L1 displayed remarkable clinical activity such as complete sustained clinical remission even in patients bearing multiple metastases. Malignant melanoma, non-small cell lung cancer or Hodgkin's lymphoma are examples of cancer entities with especially well clinical responses to immune checkpoint inhibitors. This fast-developing field is rapidly expanding the indications for immune checkpoint inhibitors and combinations with other therapeutic strategies like vessel-modulating agents or classical chemotherapy are in preclinical and clinical testing. In this article, the mechanistic principles of immune checkpoint inhibition and their clinical applications are illustrated.


Assuntos
Imunoterapia , Neoplasias/terapia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Imunoterapia/métodos
9.
Ther Umsch ; 76(4): 195-198, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498041

RESUMO

Immunotherapy - immune-related adverse events and their management Abstract. Checkpoint-Inhibition has become an important part of modern oncological treatment strategies for many patients with cancer. The development of this new class of anti-cancer drugs has begun for ten years and showed meanwhile a specific new side effect profile. Since the mode of action of checkpoint inhibitors is immune modulation the side effects are particularly different to so far established anti-cancer drugs. Because of the immunological nature of side effects, the spectrum is wide, and the symptoms are amble. Additionally, the side effects can appear at very different time points after the administration of the checkpoint inhibitor. Therefore, the recognition and the management are a new challenge for the care teams. Only if the whole care team is able to understand, diagnose and efficiently manage the side effects the therapeutic potential of this new class of anti-cancer drugs can be made useful for the patients. The article aims to provide information for the care teams to recognize and manage side effects of checkpoint-inhibitors.


Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/terapia , Humanos , Fatores Imunológicos , Oncologia , Síndromes Neurotóxicas/etiologia
10.
Expert Opin Investig Drugs ; 28(10): 821-826, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526130

RESUMO

Introduction: The conventional management of most patients with metastatic urothelial carcinoma (UC) is platinum-based chemotherapy followed by immunotherapy. Erdafitinib is an option in post-platinum patients with activating mutations in fibroblast growth factor receptor (FGFR)-3 and -2. Salvage therapy with taxanes or vinflunine has demonstrated minimal efficacy. Enfortumab Vedotin (EV), a monoclonal antibody-drug conjugate (ADC) targeting nectin-4 is under investigation in patients with advanced UC. Areas covered: This review describes the epidemiology and unmet needs of patients with metastatic UC and is focused specifically on heavily treated patients. We explore the rationale for targeting nectin 4 and the clinical development of EV; efficacy and safety data from the completed phase I and II studies are examined. Ongoing trials to definitively assess clinical outcomes in comparison to current therapy and trials exploring EV in combination are also highlighted. Expert opinion: There is an unmet need for new therapies in most patients with advanced UC and who progress after platinum and immunotherapy. EV has shown promising efficacy and safety in this population in phase 1 and 2 trials including those with poor prognostic factors such as liver metastases. Ongoing trials exploring this agent in combination will continue to advance the treatment of UC.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células de Transição/imunologia , Moléculas de Adesão Celular/imunologia , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacologia , Imunoterapia/métodos , Metástase Neoplásica , Oligopeptídeos/imunologia , Prognóstico , Neoplasias Urológicas/imunologia
11.
Cancer Immunol Immunother ; 68(9): 1417-1428, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422446

RESUMO

Systemic immunotherapy with PD-1 inhibitors is established in the treatment of metastatic melanoma. However, up to 60% of patients do not show long-term benefit from a PD-1 inhibitor monotherapy. Intralesional treatments with immunomodulatory agents such as the oncolytic herpes virus Talimogene Laherparepvec and interleukin-2 (IL-2) have been successfully used in patients with injectable metastases. Combination therapy of systemic and local immunotherapies is a promising treatment option in melanoma patients. We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a higher PD-1 expression in the inflammatory infiltrate of the tumor microenvironment in metastases from patients with subsequent treatment response. All responding patients further showed a profound increase of the absolute eosinophil count (AEC) in the blood. Our case series supports the concept that patients with initial resistance to PD-1 inhibitor therapy and injectable lesions can profit from an additional intralesional IL-2 therapy which was well tolerated. Response to this therapy is accompanied by increase in AEC and a strong T cell-based inflammatory infiltrate.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Eosinófilos/imunologia , Imunoterapia/métodos , Interleucina-2/uso terapêutico , Melanoma/terapia , Neoplasias Cutâneas/terapia , Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inflamação , Ativação Linfocitária , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/imunologia , Regulação para Cima
12.
Cancer Immunol Immunother ; 68(9): 1429-1441, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31428800

RESUMO

MHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2-MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis by blocking the VEGFR2 signaling pathway. Additionally, JZC01 promoted NK and CD8+ T cells to release IFN-γ and engaged activated lymphocytes to lysis of VEGFR2-expressing tumor cells. The in vivo anti-tumor activity of JZC01 was investigated by establishing a Lewis lung cancer cell-transplanted mouse model. It effectively reduced the tumor vascular density and increased the infiltration and activation of NK and CD8+ T cells in the tumor microenvironment. Thus, JZC01 functions in anti-tumor angiogenesis and anti-tumor immune activation, and showed improved anti-tumor efficacy combined with docetaxel, which provides a new insight into anti-tumor therapy.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos Biespecíficos/genética , Apoptose , Carcinoma Pulmonar de Lewis , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Tolerância Imunológica , Interferon gama/metabolismo , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
13.
Cancer Immunol Immunother ; 68(9): 1443-1454, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31444607

RESUMO

Immunotherapy is effective in head and neck squamous cell carcinoma (HNSCC), but only a minority of patients responds to immune checkpoint blockade (ICB). To contribute to a better understanding of the underlying immune biology, we combined histomorphological evaluation and molecular analysis of the HNSCC immune microenvironment in the TCGA cohort. Analyzing digital HE-stained slides, a method for classification of tumor infiltrating lymphocytes (TILs) in the intra-epithelial compartment (ieTILs, present vs. absent) and the stromal compartment (strTILs, high vs. low) was established. We also analyzed the abundance of eight immune cell populations (estimated from RNAseq data) and PD-L1 mRNA expression. Status of ieTILs and status of strTILs were concordant for 61%, but discordant for 39% of tumors. In univariate survival analysis, ieTILs were a positive prognostic marker for DFS in the study cohort (HR = 0.66, p = 0.015) and in the HPV- subcohort (HR = 0.68, p = 0.04), but not in the HPV + subcohort. T cells were a positive prognostic marker for DFS in the study cohort (HR = 0.80, p = 0.03) and in the HPV + subcohort (HR = 0.20, p = 0.001), but not in the HPV- subcohort. In univariate survival analysis, PD-L1 mRNA expression was neither associated with DFS nor with OS. However, in bivariate and multivariate analyses including both PD-L1 mRNA levels and T cells, PD-L1 was a negative prognostic marker of DFS and OS, while T cells remained a positive prognostic marker. In conclusion, ieTILs and strTILs were non-redundant biomarkers in HNSCC and should be evaluated separately. The identified prognostic markers should be evaluated for predictivity in ICB-treated patients.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/imunologia , Células Epiteliais/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Células Estromais/patologia , Antígeno B7-H1/genética , Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sequência de RNA , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral
14.
Cancer Immunol Immunother ; 68(9): 1467-1477, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31451841

RESUMO

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Células Dendríticas/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Células Dendríticas/transplante , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Prospectivos , Piridinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Análise de Sobrevida
15.
Presse Med ; 48(7-8 Pt 1): 859-870, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31447331

RESUMO

Non-follicular small cell lymphomas include several entities whose clinical and pathological descriptions have been refined in the last 20 years. MALT lymphoma, developed at the expense of lymphoid tissue associated with the mucosa, is usually localized to a given organ, but can also disseminate. Some patients with MALT lymphoma can be treated by eradicating the associated infectious agent, whereas local treatment should be preferred for other cases ; disseminated forms and relapsed patients are eligible for anti-CD20 antibodies associated with cytotoxic agents. Patients with mantle cell lymphoma have benefited from many advances, including the use of cytarabine and bendamustine, anti-CD20 antibodies, intensive treatments (autograft) and recently targeted therapy (ibrutinib, inhibitor or the Bruton tyrosine kinase). Patients with splenic nodal marginal zone lymphomas should be evaluated for different options, of which immunochemotherapy remains important. For all these entities, the implementation of treatments may be delayed by several years for certain groups of patients. Although considered as incurable, the prognosis of these pathologies has improved significantly and the majority of patients will be able to live for many years with often treatment-free intervals.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Fatores Etários , Idade de Início , Anticorpos Monoclonais/uso terapêutico , Diagnóstico Diferencial , Humanos , Imunoterapia/métodos , Imunoterapia/tendências , Linfoma de Zona Marginal Tipo Células B/classificação , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/epidemiologia , Linfoma de Zona Marginal Tipo Células B/terapia , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Prognóstico , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/epidemiologia , Neoplasias Esplênicas/patologia , Neoplasias Esplênicas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
16.
Presse Med ; 48(7-8 Pt 1): 850-858, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31447334

RESUMO

Follicular lymphoma, the second most common lymphoma, is characterized by its slow growth and is often considered incurable in advanced stages. Progresses in biology have contributed to better understand the complex and successive mechanisms of development of this pathology, whose diagnosis is based on a lymph node biopsy. However, the prognosis of the patients is heterogeneous and several indexes have been proposed to identify groups of patients with a similar life expectancy, in order to guide the therapeutic choices. The treatment has been modified in the last 20 years by the emergence of anti-CD20 monoclonal antibodies which constitute, alone or in combination, of the cornerstone of therapeutic management. After staging using, in particular, 18-fluorodeoxyglucose positron emission tomography, the therapeutic strategy will be adapted for each patient, ranging from simple watchful waiting to a combination of chemotherapy and anti-CD20 antibodies. Relapses (which often require a new lymph node biopsy to eliminate a possible histological transformation into an aggressive lymphoma with poorer prognosis) remain common but are still accessible to effective therapeutic interventions. Thanks to these advances, the median life expectancy of patients with follicular lymphoma now exceeds 15 years.


Assuntos
Linfoma Folicular , Biópsia , Diagnóstico Diferencial , Humanos , Imunofenotipagem/métodos , Imunoterapia/métodos , Imunoterapia/tendências , Expectativa de Vida , Linfoma Folicular/diagnóstico , Linfoma Folicular/epidemiologia , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Técnicas de Diagnóstico Molecular , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Prognóstico , Taxa de Sobrevida , Terapias em Estudo/métodos , Terapias em Estudo/tendências
17.
Presse Med ; 48(7-8 Pt 1): 825-831, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31447337

RESUMO

Diagnosis criteria have been revised in 2014 and allow the treatment of some asymptomatic patients. Since 2015, a new prognostic score includes tumor plasma cells chromosomal abnormalities. It helps in the distinction between "standard risk" and "high risk" myelomas. Scanner, MRI and Pet Scan are the radiological reference exams to evaluate bone involvement. Alkylating agents, immunomodulators, proteasome inhibitors, and monoclonal antibodies became the most important antitumoral treatments. Risk notion will become more and more important for therapeutic choices. These choices will depend on residual disease evaluation. The next decade will be the immunotherapies development decade.


Assuntos
Detecção Precoce de Câncer/tendências , Oncologia/tendências , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Terapias em Estudo/tendências , Anticorpos Monoclonais/uso terapêutico , Terapia Combinada/tendências , Detecção Precoce de Câncer/métodos , Detecção Precoce de Câncer/normas , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Imunoterapia/tendências , Oncologia/métodos , Oncologia/normas , Mieloma Múltiplo/patologia , Guias de Prática Clínica como Assunto , Prognóstico , Terapias em Estudo/métodos
18.
Expert Opin Investig Drugs ; 28(9): 757-770, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31412742

RESUMO

Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.


Assuntos
Antineoplásicos/farmacologia , Drogas em Investigação/farmacologia , Neoplasias da Bexiga Urinária/terapia , Animais , Antineoplásicos/administração & dosagem , Vacina BCG/administração & dosagem , Biomarcadores Tumorais/metabolismo , Cistectomia/métodos , Sistemas de Liberação de Medicamentos , Drogas em Investigação/administração & dosagem , Humanos , Imunoterapia/métodos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neoplasias da Bexiga Urinária/patologia
19.
Anticancer Res ; 39(8): NP, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366564
20.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(8): 596-601, 2019 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-31378021

RESUMO

Objective: To evaluate the feasibility of cell-free tumor DNA in pleural effusion supernatant for assessing the tumor mutational burden (TMB) of advanced lung cancers. Methods: From December 2016 to August 2018, 34 lung cancer patients (19 males and 15 females) with pleural effusion were enrolled at Zhongshan Hospital, Fudan University. The median age of the patients was 65 (range, 34-85) years. Before systemic or local antitumor therapy, tumor specific mutations in tumor tissue, pleural effusion supernatant, pleural effusion sediment, and plasma samples from these patients were examined using targeted next-generation sequencing, and TMB levels were calculated respectively. Subgroup analysis was based on smoking history and driver mutation status. Statistical differences were determined using SPSS 16.0 software, and individual groups were compared using the one-way analysis of variance (ANOVA) and LSD-t test. Results: The median TMB level of pleural effusion supernatant was 6.23 mutations/Mb, similar to that of tumor tissue (6.23 vs 6.86 mutations/Mb, t=1.174, P=0.245), but significantly higher than that of pleural effusion sediment (2.49 mutations/Mb, t=3.044, P=0.003) and plasma (2.49 mutations/Mb, t=2.464, P=0.016). Compared with tumor tissue in TMB assessment, pleural effusion supernatant had a positive percentage agreement of 52% (9/17), and a negative percentage agreement of 65% (11/17). Subgroup analysis showed that the TMB level was higher in smokers (n=11) than that in non-smokers (n=23, 14.4 vs 5.4 mutations/Mb, t=3.238, P=0.003). Conclusion: For advanced lung cancer patients with pleural effusion, pleural effusion supernatant is a promising substitute to tumor tissue for TMB assessment, which is a potential biomarker for immunotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , DNA Tumoral Circulante , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Derrame Pleural , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA