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1.
Medicine (Baltimore) ; 99(41): e22567, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031304

RESUMO

BACKGROUND: We put the meta-analysis into practice to reveal the relationship between the incidence risk of immune-related pneumonitis and the use of programmed cell death-1 (PD-1) and ligand 1 (PD-L1) inhibitors related pneumonitis in cancer patients. METHOD: The meta-analysis was put into practice according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Odds ratio (OR) was evaluated by random effect model. RESULTS: After screening and eligibility assessment, 33 clinical trials involving 19,854 patients were selected and used for the final meta-analysis after selection criteria checked. Compared with chemotherapy, the use of PD-1/PD-L1 inhibitors alone increased the incidence risk of all-grade (OR = 4.29, 95% confidence interval: [2.97, 6.19], P < .00001) and grade 3 to 5 immune-related pneumonitis (OR = 3.53, 95% confidence interval: [2.04, 6.11], P < .00001). Similar trend could also be found when PD-1/PD-L1 inhibitors were prescribed alone or in combination with other anti-tumor therapies. CONCLUSION: Whether PD-1/PD-L1 inhibitors were used alone or combined with other antitumor drugs, the incidence risk of immune-related pneumonitis would be increased.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Pneumonia/imunologia
2.
Immunotherapy ; 12(15): 1133-1138, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32900245

RESUMO

Background: Little is known about the 2019 novel coronavirus disease (COVID-19) course and outcomes in patients receiving immunotherapy. Here we describe a metastatic Merkel cell carcinoma patient with a severe acute respiratory syndrome coronavirus 2 infection while receiving pembrolizumab. Case presentation: A 66-year-old man, with a metastatic Merkel cell carcinoma receiving pembrolizumab, presented with fever. Chest computed tomography (CT) showed pulmonary ground-glass opacities, suggesting viral or immuno-related etiology. On day 7, the patient was hospitalized due to dyspnea and worsening of the radiological findings. Real time polymerase chain reaction (RT-PCR) testing confirmed COVID-19. The patient developed acute respiratory distress syndrome and acute kidney injury. Hydroxychloroquine was administered for 5 days, but discontinued after supraventricular extrasystoles. Clinical improvement allowed the patient's discharge after 81 days of hospitalization. Conclusion: A careful evaluation of oncologic patients receiving immunotherapy during the COVID-19 pandemic is of utmost importance.


Assuntos
Carcinoma de Célula de Merkel/terapia , Infecções por Coronavirus/diagnóstico , Imunoterapia , Pneumonia Viral/diagnóstico , Neoplasias Cutâneas/terapia , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Betacoronavirus , Carcinoma de Célula de Merkel/complicações , Carcinoma de Célula de Merkel/patologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Humanos , Imunoterapia/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/patologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
4.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
5.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
6.
Medicine (Baltimore) ; 99(37): e22153, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925773

RESUMO

BACKGROUND: Immune checkpoint blockade (ICB) brings hope to many late-stage cancer patients yet its marker for response remains elusive. METHODS: We developed a hypothesis that treatment-related adverse events (TrAEs) could predict objective response rate (ORR) to ICB. We plotted ORR against corresponding any and grade 3 to 5 (G3-5) TrAEs across a variety of cancer types by performing a meta-analysis using linear regression. RESULTS: We identified 113 eligible studies encompassing 25 types of malignancies that were treated with ICB or ICB-based regimes. A significant linear correlation was observed for any and severe TrAEs, respectively. The correlation coefficient was 0.57 (r = 0.324) for any TrAE and 0.61 (r = 0.37) for G3-5 TrAE. For melanoma, the correlation coefficient was 0.81 (r = 0.57) for any TrAE and 0.65 (r = 0.42) for G3-5 TrAEs. For RCC, the correlation coefficient was 0.86 (r = 0.74) for any TrAE and 0.91 (r = 0.83) for G3-5 TrAE. For NSCLC, the correlation coefficient was 0.55 (r = 0.3) for any TrAE and 0.74 (r = 0.86) for G3-5 TrAE. For UC, the correlation coefficient was 0.47 (r = 0.68) for any TrAE and 0.27 (r = 0.52) for G3-5 TrAE, yet the correlation was insignificant for severe AEs. CONCLUSION: Our findings suggest that over half of ICB responses could be reflected by any adverse events and ∼60% of responses could be reflected by severe AEs. Further validation is needed in individual trials.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Estadiamento de Neoplasias , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Análise de Sobrevida , Resultado do Tratamento
8.
Nat Commun ; 11(1): 3806, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732922

RESUMO

Most triple-negative breast cancer (TNBC) patients fail to respond to T cell-mediated immunotherapies. Unfortunately, the molecular determinants are still poorly understood. Breast cancer is the disease genetically linked to a deficiency in autophagy. Here, we show that autophagy defects in TNBC cells inhibit T cell-mediated tumour killing in vitro and in vivo. Mechanistically, we identify Tenascin-C as a candidate for autophagy deficiency-mediated immunosuppression, in which Tenascin-C is Lys63-ubiquitinated by Skp2, particularly at Lys942 and Lys1882, thus promoting its recognition by p62 and leading to its selective autophagic degradation. High Tenascin-C expression is associated with poor prognosis and inversely correlated with LC3B expression and CD8+ T cells in TNBC patients. More importantly, inhibition of Tenascin-C in autophagy-impaired TNBC cells sensitizes T cell-mediated tumour killing and improves antitumour effects of single anti-PD1/PDL1 therapy. Our results provide a potential strategy for targeting TNBC with the combination of Tenascin-C blockade and immune checkpoint inhibitors.


Assuntos
Autofagia/imunologia , Linfócitos T CD8-Positivos/imunologia , Tenascina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Evasão Tumoral/imunologia , Animais , Antineoplásicos Imunológicos/farmacologia , Autofagia/genética , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunoterapia Adotiva , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/terapia , Evasão Tumoral/genética
9.
Medicine (Baltimore) ; 99(34): e21718, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846790

RESUMO

BACKGROUND: Programmed death receptor-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have been demonstrated to improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) compared with chemotherapy. However, there were still some non-responders. Thus, how to effectively screen the responder may be an important issue. Recent studies revealed the immune-related indicator, neutrophil-lymphocyte ratio (NLR), may predict the therapeutic effects of anti-PD1/PD-L1 antibodies; however, the results were controversial. This study was to re-evaluate the prognostic potential of NLR for NSCLC patients receiving PD1/PD-L1 inhibitors by performing a meta-analysis. METHODS: Eligible studies were identified by searching online databases of PubMed, EMBASE and Cochrane Library. The predictive values of NLR for overall survival, (OS), progression free survival (PFS) and overall response rate (ORR) were estimated by hazard ratio (HR) with 95% confidence interval (CI). RESULTS: Twenty-four studies involving 2196 patients were included. The pooled analysis demonstrated that elevated NLR before PD-1/PD-L1 inhibitor treatment was a predictor of poor OS (HR = 2.17; 95% CI: 1.64 - 2.87, P < .001), PFS (HR = 1.54; 95% CI: 1.34 - 1.78, P < .001) and low ORR (HR = 0.64; 95% CI: 0.44 - 0.95, P = .027) in NSCLC patients. Subgroup analysis revealed the predictive ability of NLR for OS and PFS was not changed by ethnicity, sample size, cut-off, HR source, study design or inhibitor type (except the combined anti-PD-L1 group); while its association with ORR was only significant when the cut-off value was less than 5 and the studies were prospectively designed. CONCLUSION: Our findings suggest patients with lower NLR may benefit from the use of PD-1/PD-L1 inhibitors to prolong their survival period.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Testes Hematológicos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/patologia , Linfócitos , Neutrófilos
10.
Nat Commun ; 11(1): 3858, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737343

RESUMO

Checkpoint blockade therapy has provided noteworthy benefits in multiple cancers in recent years; however, its clinical benefits remain confined to 10-40% of patients with extremely high costs. Here, we design an ultrafast, low-temperature, and universal self-assembly route to integrate immunology-associated large molecules into metal-organic-framework (MOF)-gated mesoporous silica (MS) as cancer vaccines. Core MS nanoparticles, acting as an intrinsic immunopotentiator, provide the niche, void, and space to accommodate antigens, soluble immunopotentiators, and so on, whereas the MOF gatekeeper protects the interiors from robust and off-target release. A combination of MOF-gated MS cancer vaccines with systemic programmed cell death 1 (PD-1) blockade therapy generates synergistic effects that potentiate antitumour immunity and reduce the effective dose of an anti-PD-1 antibody to as low as 1/10 of that for PD-1 blockade monotherapy in E.G7-OVA tumour-bearing mice, with eliciting the robust adaptive OVA-specific CD8+ T-cell responses, reversing the immunosuppressive pathway and inducing durable tumour suppression.


Assuntos
Anticorpos Neutralizantes/farmacologia , Vacinas Anticâncer/farmacologia , Linfoma/terapia , Estruturas Metalorgânicas/farmacologia , Nanopartículas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Citotoxicidade Imunológica , Composição de Medicamentos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Estruturas Metalorgânicas/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptor de Morte Celular Programada 1/imunologia , Dióxido de Silício/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Bull Cancer ; 107(7-8): 830-842, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32758364

RESUMO

Immune checkpoint inhibitors (ICI) have revolutionized oncological management in several tumor types, allowing prolonged tumoral responses. Thus, they are administered over long periods of time and can give specific autoimmune adverse reactions that may have a potential impact on quality of life (QoL). Most of phase III trials with ICI have included an assessment of QoL. In metastatic setting, in comparison with chemotherapy or targeted therapies, they indicate an absence of degradation of the QoL scores or even an improvement of these scores. In adjuvant setting, the deterioration of QoL scores is not clinically significant, regardless of the ICI used. In addition, there is no impairment of quality of life in patients with prolonged treatment duration. However, the measurement of QoL under ICI remains a challenge because of the specificities of these treatments and adapted measurement scales are being developed to improve the assessment of the impact of these treatments on patients' QoL.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Qualidade de Vida , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Inquéritos Epidemiológicos , Humanos , Imunoterapia Adotiva/efeitos adversos , Terapia de Alvo Molecular/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
Cancer Treat Rev ; 89: 102084, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32738738

RESUMO

Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Neoplasias/genética , Neoplasias/terapia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase III como Assunto , Testes Genéticos , Humanos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Cancer Treat Rev ; 89: 102085, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32771858

RESUMO

Immune checkpoint inhibitors (ICIs) represent one of the main steps forward for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC), without oncogenic driver alterations. Despite this recent progress, only a minority of patients achieve a broad and durable benefit and another proportion report poor survival and sometimes fast disease progression, confirming the need to optimise the patient's selection. To date, several issues are unsolved about how to personalise the immunotherapy treatment for individual patients. In this review, analysing data from pivotal randomised clinical trials (RCTs), we discuss patient baseline clinical and demographic features, including sex, age, ECOG performance status, smoking habit and specific site of metastases (liver, bone and brain) that may influence the efficacy outcomes in patients treated with ICIs. The high performance of the ICIs blurred the vision on different efficacy-limiting factors, which require extensive evaluation to improve the understanding ofthe tumour-specificimmune response, in which clinical drivers could be useful for better patient stratification.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
15.
Nat Commun ; 11(1): 3946, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770055

RESUMO

Melanomas can switch to a dedifferentiated cell state upon exposure to cytotoxic T cells. However, it is unclear whether such tumor cells pre-exist in patients and whether they can be resensitized to immunotherapy. Here, we chronically expose (patient-derived) melanoma cell lines to differentiation antigen-specific cytotoxic T cells and observe strong enrichment of a pre-existing NGFRhi population. These fractions are refractory also to T cells recognizing non-differentiation antigens, as well as to BRAF + MEK inhibitors. NGFRhi cells induce the neurotrophic factor BDNF, which contributes to T cell resistance, as does NGFR. In melanoma patients, a tumor-intrinsic NGFR signature predicts anti-PD-1 therapy resistance, and NGFRhi tumor fractions are associated with immune exclusion. Lastly, pharmacologic NGFR inhibition restores tumor sensitivity to T cell attack in vitro and in melanoma xenografts. These findings demonstrate the existence of a stable and pre-existing NGFRhi multitherapy-refractory melanoma subpopulation, which ought to be eliminated to revert intrinsic resistance to immunotherapeutic intervention.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Melanoma/tratamento farmacológico , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores de Fator de Crescimento Neural/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Animais , Antineoplásicos Imunológicos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , RNA-Seq , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Science ; 369(6506): 936-942, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820119

RESUMO

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.


Assuntos
Antígenos de Neoplasias/imunologia , Bacteriófagos/imunologia , Streptococcus faecium ATCC 9790/virologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas da Cauda Viral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , Ciclofosfamida/uso terapêutico , Epitopos/imunologia , Fezes/virologia , Antígenos H-2/imunologia , Humanos , Camundongos , Neoplasias/dietoterapia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteínas da Cauda Viral/uso terapêutico
17.
Nat Commun ; 11(1): 4011, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782249

RESUMO

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.


Assuntos
Cinurenina/imunologia , Macrófagos/imunologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Tolerância Imunológica , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
18.
Front Immunol ; 11: 1708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754163

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is the pathogen that causes coronavirus disease 2019 (COVID-19). As of 25 May 2020, the outbreak of COVID-19 has caused 347,192 deaths around the world. The current evidence showed that severely ill patients tend to have a high concentration of pro-inflammatory cytokines, such as interleukin (IL)-6, compared to those who are moderately ill. The high level of cytokines also indicates a poor prognosis in COVID-19. Besides, excessive infiltration of pro-inflammatory cells, mainly involving macrophages and T-helper 17 cells, has been found in lung tissues of patients with COVID-19 by postmortem examination. Recently, increasing studies indicate that the "cytokine storm" may contribute to the mortality of COVID-19. Here, we summarize the clinical and pathologic features of the cytokine storm in COVID-19. Our review shows that SARS-Cov-2 selectively induces a high level of IL-6 and results in the exhaustion of lymphocytes. The current evidence indicates that tocilizumab, an IL-6 inhibitor, is relatively effective and safe. Besides, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, intravenous immunoglobulin, and antimalarial agents could be potentially useful and reliable approaches to counteract cytokine storm in COVID-19 patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Interleucina-6/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Infecções por Coronavirus/virologia , Hemoperfusão/métodos , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Interleucina-6/antagonistas & inibidores , Camundongos , Pandemias , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores
19.
Medicine (Baltimore) ; 99(32): e21613, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769920

RESUMO

BACKGROUND: Programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors are immune therapies that have shown great promise in the treatment of multiple cancers. However, immune-related adverse events of PD-1 and PD-L1 inhibitors may limit their use in non-small cell lung cancer (NSCLC). Given the rising number of clinical trials in recent years, it is essential to perform a meta-analysis to provide assess the cardiotoxicity of PD-1/ PD-L1 inhibitors in NSCLC therapy. METHOD AND ANALYSIS: The ClinicalTrials.gov, Embase, PubMed, and Cochrane Central Register of Controlled Trials repositories will be searched from their inception to December 2019. The bibliography of the searching process will be imported into Endnote X9 software. Two reviewers independently will screen the literature, extract data, and conduct the risk of bias for every added study. The data analysis will be analyzed using Stata15.0 software. Specific adverse cardiac events will be identified, with particular attention on atrial fibrillation, cardiac arrest, cardiac failure, and pericarditis. This review will be performed as per the Preferred Reporting Item for Systematic Review and meta-analysis statement recommendations. ETHICS AND DISSEMINATION: This study will provide support for the cardiotoxicity linked to the treatment of NSCLC using PD-1/PD-L1 inhibitors. The data in the meta-analysis will be retrieved from completed and published clinical trials; therefore, ethical review and patient informed consent will not be required. PROSPERO NUMBER: CRD42020156397.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cardiotoxicidade/etiologia , Protocolos Clínicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/complicações , Cardiotoxicidade/fisiopatologia , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
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