Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 4.319
Filtrar
1.
Recent Results Cancer Res ; 214: 169-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473853

RESUMO

Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8+ T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8+ T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.


Assuntos
Linfócitos T CD8-Positivos/citologia , Imunoterapia , Melanoma/terapia , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais , Antígeno B7-H1 , Europa (Continente) , Humanos , Microambiente Tumoral
2.
Medicine (Baltimore) ; 98(38): e17257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567999

RESUMO

Recent availability of immune checkpoint inhibitors has facilitated research involving programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1). However, the incidence and clinical implication of PD-1 and PD-L1 expression in prostate cancer remain poorly understood. The current study aimed to determine the status of PD-1/PD-L1 expression in prostate cancer specimens and its prognostic significance.We immunohistochemically stained for PD-1 and PD-L1 in our tissue microarray (TMA) consisting of radical prostatectomy specimens. The expression of PD-1/PD-L1 was designated as positive when moderate to strong staining or weak staining was seen in at least 1% or 10%, respectively, of tumor cells and/or associated immune cells. We then evaluated the relationship between the expression of each protein and clinicopathological features available for our patient cohort.PD-1 and PD-L1 were positive in 3 (1.5%) and 1 (0.5%) of 201 non-neoplastic prostate tissues, and also in 17 (7.7%) and 29 (13.2%) of 220 prostate cancers, respectively. PD-1 and PD-L1 were also expressed in tumor-infiltrating lymphocytes/macrophages in 172 (78.2%) and 33 (15.0%) cases, respectively. PD-L1 expression in tumor cells was more often seen in high pT stage (pT2: 10.8% vs pT3/4: 20.4%; P = .072; pT2/3a: 11.4% vs pT3b/4: 31.6%; P = .013) or lymph node-positive (pN0: 10.1% vs pN1: 27.3%; P = .086) cases, whereas PD-1 expression in tumor cells was not significantly associated with pT/pN stage. In addition, there were no statistically significant associations between PD-1/PD-L1 expression in tumor cells or tumor-infiltrating lymphocytes/macrophages versus patient age, preoperative prostate-specific antigen level, or Gleason score. Kaplan-Meier analysis coupled with log-rank test further revealed no significant associations between PD-1/PD-L1 expression in tumor cells (P = .619/P = .315), tumor-infiltrating lymphocytes/macrophages (P = .954/P = .155), or either or both of them (P = .964/P = .767) versus disease recurrence after radical prostatectomy.PD-1/PD-L1 expression was detected in a subset of prostate cancers. In particular, PD-L1 expression was considerably up-regulated in nonorgan-confined tumors. However, PD-1/PD-L1 expression in our TMA was found to be not very helpful in predicting tumor recurrence in prostate cancer patients who underwent radical prostatectomy.


Assuntos
Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Próstata/metabolismo , Antígeno B7-H1/imunologia , Biomarcadores , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Análise Serial de Tecidos
3.
Zhonghua Gan Zang Bing Za Zhi ; 27(9): 732-736, 2019 Sep 20.
Artigo em Chinês | MEDLINE | ID: mdl-31594104

RESUMO

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Humanos , Receptor de Morte Celular Programada 1/metabolismo
4.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593084

RESUMO

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos
5.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
7.
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
8.
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
9.
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
10.
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
11.
Anticancer Res ; 39(9): 4995-5001, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519606

RESUMO

BACKGROUND/AIM: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) combined with non-myeloablative chemotherapy (NMA) has been shown to prolong survival in patients with metastatic disease. MATERIALS AND METHODS: Tissue harvesting was performed form a variety of sites. TILs were isolated, expanded and infused with bolus high-dose IL-2. RESULTS: Between 2008 and 2018, 242 lesions were resected for TILs harvesting from a range of sites form 196 patients without mortality and with minimal morbidity. Of those harvested, 75 were unable to complete therapy because of clinical deterioration during the wait period. Of 121 evaluable treated patients, there was no effect of metastatic site biopsied on the mean fold TIL expansion. Those receiving prior ipilimumab had a higher TIL fold expansion but a lower TIL fold expansion than those exposed to anti-PD1 therapy. CONCLUSION: Harvesting may be safely performed with successful TIL expansion from most sites. Prior check point inhibitory immunotherapy may potentially influence TIL fold expansion.


Assuntos
Imunoterapia Adotiva , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/terapia , Adolescente , Adulto , Idoso , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Feminino , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto Jovem
12.
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
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 641-648, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537249

RESUMO

Objective To investigate the expression of programmed cell death 1 (PD-1) and inducible costimulatory molecules (ICOS) on peripheral T lymphocytes of patients with rheumatoid arthritis (RA) and to determine its relationship with disease severity. Methods The study included 30 RA patients and 26 healthy people. Flow cytometry was used to detect the ratio of CD3+CD8+ effector memory T cells (Tem) and follicular helper T (Tfh) cells in peripheral blood, and then to detect the proportion of PD-1 and ICOS-positive cells in lymphocyte subsets. Correlation between them and 28 joint disease activity scores (DAS28) was assessed by Spearman correlation analysis. Results The absolute number of Tem and Tfh cells in the RA group was higher than that in the healthy group. The expression of ICOS and PD-1 in the RA group was higher than that in the healthy group. There was a positive correlation between the expression of ICOS and PD-1 on peripheral CD3+CD8+ Tem and Tfh cells and DAS28 in RA group. Conclusion PD-1 and ICOS on peripheral CD3+CD8+ Tem and Tfh cells may be involved in the development of RA and may be an indicator of RA activity.


Assuntos
Artrite Reumatoide/patologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Artrite Reumatoide/metabolismo , Humanos
14.
Cancer Immunol Immunother ; 68(10): 1635-1648, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31549214

RESUMO

Pancreatic cancer has been termed a 'recalcitrant cancer' due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate growth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown to prolong survival of patients with pancreatic cancer. Here, we report that PAS vaccination monotherapy elicits both a humoral and cellular immune response when used in immune competent mice-bearing pancreatic tumors and that PAS monotherapy produced a marked T-cell activation and influx of CD8 + lymphocytes into pancreatic tumors. Isolated peripheral lymphocytes elicited cytokine release upon re-stimulation with gastrin in vitro demonstrating specificity of immune activation for the target peptide. Combination therapy with PAS and PD-1 Ab activated CD4 -/CD8 - TEMRA cells important in T-cell-mediated tumor death and memory. Tumors of mice treated with PAS (250 µg) or PAS (100 and 250 µg) in combination with a PD-1 Ab were significantly smaller compared to tumors from PBS or PD-1 Ab-treated mice. When PAS was given in combination with PD-1 Ab, tumors had less fibrosis, fewer inhibitory Treg lymphocytes, and fewer tumor-associated macrophages. These findings reveal a novel approach to improve treatment strategies for pancreatic cancer.


Assuntos
Vacinas Anticâncer/imunologia , Gastrinas/imunologia , Neoplasias Pancreáticas/terapia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral , Vacinação , Animais , Linhagem Celular Tumoral , Memória Imunológica , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Linfócitos T/imunologia
15.
Cancer Immunol Immunother ; 68(10): 1585-1596, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31515670

RESUMO

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naïve CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Idoso , Proteína C-Reativa/análise , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Renais/imunologia , Feminino , Receptor Celular 2 do Vírus da Hepatite A/sangue , Humanos , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade
16.
Cancer Sci ; 110(10): 3079-3088, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432594

RESUMO

Chimeric antigen receptor-engineered T (CAR-T)-cell therapy holds significant promise for the treatment of hematological malignancies, especially for B-cell leukemia and lymphoma. However, its efficacy against non-hematological malignancies has been limited as a result of several biological problems characteristic of the tumor microenvironment of solid tumors. One of the main hurdles is the heterogeneous nature of tumor-associated antigens (TAA) expressed in solid tumors. Another hurdle is the inefficient activation and limited persistence of CAR-T cells, mainly as a result of T-cell exhaustion caused by immunosuppressive factors in the tumor microenvironment. In the present study, to address these problems, we engineered CAR-T cells to produce antagonistic anti-programmed cell death protein 1 (PD-1) single-chain variable fragment (scFv), by which PD-1-dependent inhibitory signals in CAR-T cells and adjacent tumor-specific non-CAR-T cells are attenuated. In mouse solid tumor models, PD-1 scFv-producing CAR-T cells induced potent therapeutic effects superior to those of conventional CAR-T cells, along with a significant reduction of apoptotic cell death not only in CAR-T cells themselves but also in TAA-specific T cells in the tumor tissue. In addition, the treatment with anti-PD-1 scFv-producing CAR-T cells resulted in an increased concentration of PD-1 scFv in tumor tissue but not in sera, suggesting an induction of less severe systemic immune-related adverse events. Hence, the present study developed anti-PD-1 scFv-producing CAR-T cell technology and explored its cellular mechanisms underlying potent antitumor efficacy.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Cadeia Única/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Técnicas de Cocultura , Masculino , Camundongos , Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Medicine (Baltimore) ; 98(35): e16972, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464942

RESUMO

Single nuclear polymorphism (SNP) of programmed cell death 1 (PD-1) was reported associated with hepatitis B virus (HBV) infection, but the SNP sites studied were limited. Whether the combination of 2 or more SNP sites could better represent the relationship between PD-1 SNP and HBV infection was not studied.Eight hundred ninety-eight HBV-infected patients (222 asymptomatic carriers [AsC], 276 chronic hepatitis B, 105 acute-on-chronic liver failure, and 295 liver cirrhosis) and 364 health controls of South China were enrolled in this study. Four PD-1 SNPs (rs10204525, rs2227982, rs41386349, and rs36084323) were selected and detected by TaqMan probe. The frequency of allele, genotype, and combination of different SNPs were compared between different groups.For allele frequency analysis, G allele of rs10204525 was protective factor (odds ratio (OR) = 0.823, 95% confidence interval (CI) = 0.679-0.997, P = .046) and T allele of rs2227982 was predisposing factor (OR = 1.231, 95% CI = 1.036-1.463, P = .018) in HBV infection. When analyzed in genotype frequency, the genotype GG of rs10204525 and CC of rs2227982 were protective factor of HBV infection. Combination of rs10204525 GG and rs2227982 CC was potent protective factor of HBV infection (OR = 0.552, 95% CI = 0.356-0.857, P = .007) and was also associated with lower HBV load (OR = 0.201, 95% CI = 0.056-0.728, P = .008) in AsC. The 4 SNP sites were not associated with progression of HBV-related liver disease.Rs10204525 and rs2227982 of PD-1 associate with HBV infection and combination of the 2 SNP sites can better predict host susceptibility in HBV infection.


Assuntos
Hepatite B/genética , Receptor de Morte Celular Programada 1/genética , Fatores Etários , Alelos , Estudos de Casos e Controles , China/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Testes de Função Hepática , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Fatores Sexuais
18.
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
19.
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
20.
JAMA ; 322(8): 764-774, 2019 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-31454018

RESUMO

Importance: Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations: Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance: Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Pontos de Checagem do Ciclo Celular , Genes erbB-1 , Humanos , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Intervalo Livre de Progressão , Taxa de Sobrevida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA