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1.
Ann Palliat Med ; 10(8): 9015-9024, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488388

RESUMO

BACKGROUND: Tumor of the digestive system is a common malignancy with high morbidity and mortality. Although programmed cell death-1 (PD-1) inhibitors have become an effective treatment strategies for many kinds of tumors, there is still some uncertainty in digestive tumors, including: (I) therapeutic effects of PD-1 inhibitors are relatively limited; (II) responses of digestive system tumors to immunotherapies are highly heterogeneous. In the present study, we investigated the outcomes of PD-1 inhibitors for digestive system tumors in Chinese patients to analyze factors that may affect the effects of immunotherapies in digestive system tumors. METHODS: Data were obtained from the Hospital Information System (HIS) of the Department of Digestive Oncology (Henan Cancer Hospital) between January 2019 and December 2019. Inclusion criteria included patients receiving the same PD-1 inhibitor continuously for advanced or recurrent/metastatic digestive system tumors. Indicators including age, sex, clinical diagnosis, height, weight, gene status, PD-1 inhibitors, treatment regimen, medication cycle, efficacy evaluation results, and adverse reactions were analyzed retrospectively. The clinical outcomes were progression-free survival (PFS) and safety. RESULTS: A total of 2,767 patients were discharged from HIS, of which 64 (37 male/27 female) were included in this study. Thirty-eight (59.4%) of the patients were aged <60 years. Tumors included esophageal, gastric, liver, colorectal, and pancreatic cancer. Up until 30 June 2020, 51 patients were followed up to median progression-free survival (PFS), which was 5 months; the longest PFS was 18.5 months. There was no statistical significance in grouping according to sex, age and body mass index. Nevertheless, the median PFS differed statistically between monotherapy (9.4 months) versus combined therapy (4.7 months), and Cox regression analysis suggested that patients might benefit more from monotherapy than combined therapy. The incidence of adverse reactions was 47.7%, with thyroid dysfunction the most common adverse reaction. The incidence of grade 3-4 adverse reactions was 9.2% and mainly included pulmonary infection, immune-associated hepatitis, and severe oral ulcers. CONCLUSIONS: In digestive tumors, especially for second-line treatment and beyond, PD-1 monotherapy might be more beneficial than combined therapy. However, this might be related to the patient's tolerance. Large-sample prospective studies are needed for confirmation.


Assuntos
Neoplasias do Sistema Digestório , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , China , Neoplasias do Sistema Digestório/tratamento farmacológico , Feminino , Humanos , Masculino , Estudos Retrospectivos
2.
Nat Commun ; 12(1): 4852, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381028

RESUMO

Oncogenic activation of KRAS and its surrogates is essential for tumour cell proliferation and survival, as well as for the development of protumourigenic microenvironments. Here, we show that the deubiquitinase USP12 is commonly downregulated in the KrasG12D-driven mouse lung tumour and human non-small cell lung cancer owing to the activation of AKT-mTOR signalling. Downregulation of USP12 promotes lung tumour growth and fosters an immunosuppressive microenvironment with increased macrophage recruitment, hypervascularization, and reduced T cell activation. Mechanistically, USP12 downregulation creates a tumour-promoting secretome resulting from insufficient PPM1B deubiquitination that causes NF-κB hyperactivation in tumour cells. Furthermore, USP12 inhibition desensitizes mouse lung tumour cells to anti-PD-1 immunotherapy. Thus, our findings propose a critical component downstream of the oncogenic signalling pathways in the modulation of tumour-immune cell interactions and tumour response to immune checkpoint blockade therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Ubiquitina Tiolesterase/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiocinas/metabolismo , Regulação para Baixo , Humanos , Tolerância Imunológica , Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Proteína Fosfatase 2C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores
3.
Nat Med ; 27(8): 1410-1418, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34385708

RESUMO

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. Patients received cyclophosphamide and fludarabine lymphodepletion, TIL infusion and interleukin-2, followed by maintenance nivolumab. The end point of safety was met according to the prespecified criteria of ≤17% rate of severe toxicity (95% confidence interval, 3-29%). Of 13 evaluable patients, 3 had confirmed responses and 11 had reduction in tumor burden, with a median best change of 35%. Two patients achieved complete responses that were ongoing 1.5 years later. In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
4.
FASEB J ; 35(9): e21750, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34424568

RESUMO

Success of adoptive cell therapy mainly depends on the ability of immune cells to persist and function optimally in the immunosuppressive tumor microenvironment. Although present at the cancer site, immune cells become exhausted and/or inhibited, due to the presence of inhibitory receptors such as PD-L1 on malignant cells. Novel genetic strategies to manipulate the PD1/PD-L1 axis comprise (i) PD-1 reversion where the receptor intracellular domain is replaced with an activating unit, (ii) the use of anti-PD-L1 CAR or (iii) the disruption of the PD-1 gene. We here present an alternative strategy to equip therapeutic cells with a truncated PD-1 (tPD-1) to abrogate PD-1/PD-L1 inhibition. We show that engagement of tPD-1 with PD-L1-positive tumor unleashes NK-92 activity in vitro. Furthermore, this binding was sufficiently strong to induce killing of targets otherwise not recognized by NK-92, thus increasing the range of targets. In vivo treatment with NK-92 tPD-1 cells led to reduced tumor growth and improved survival. Importantly, tPD-1 did not interfere with tumor recognition in PD-L1 negative conditions. Thus, tPD-1 represents a straightforward method for improving antitumor immunity and revealing new targets through PD-L1 positivity.


Assuntos
Antígeno B7-H1/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Evasão Tumoral/imunologia , Animais , Adesão Celular , Engenharia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Engenharia Genética , Humanos , Camundongos , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Lancet Oncol ; 22(9): 1265-1274, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34391508

RESUMO

BACKGROUND: Numerous ongoing trials are testing anti-PD-1-based or anti-PD-L1-based cancer treatment combinations. Understanding the toxicity profiles of treatment-related adverse events is essential. The aim of this study was to comprehensively investigate the incidences and profiles of treatment-related adverse events across different combination therapies. METHODS: We did a systematic review and meta-analysis comparing different chemotherapy, targeted therapy, immunotherapy, and radiotherapy combinations with PD-1 or PD-L1 inhibitors. We searched Pubmed, Embase, and Cochrane databases for articles published in English between Jan 1, 2000, and May 21, 2020, investigating globally approved PD-1 or PD-L1 inhibitor-based combination therapies. Only prospective trials reporting overall incidence or tabulated data of treatment-related adverse events were included. Trials investigating sequential therapies, comprising three or more classes of therapies, and enrolling less than ten patients were excluded. The primary outcomes were overall incidences and profiles for all-grade and grade 3 or higher treatment-related adverse events by random-effect models. Heterogeneity between studies was assessed with I2 statistics. The summary measures for main outcomes are incidences (95% CI). The 95% CI were calculated together with the incidence through a random-effects model with a logit transformation. The protocol is registered with PROSPERO (CRD42020189617). FINDINGS: We identified 2540 records, of which 161 studies (17 197 patients) met the inclusion criteria. The overall incidence of treatment-related adverse events in the chemotherapy combination was 97·7% (95% CI 96·4-98·5; I2=75%) for all-grade adverse events and 68·3% (60·7-75·0; I2=93%) for grade 3 or higher adverse events; in the targeted therapy combination was 94·5% (90·7-96·8; I2=86%) for all-grade adverse events and 47·3% (37·3-57·5; I2=93%) for grade 3 or higher adverse events; in the immunotherapy combination was 86·8% (80·9-91·1; I2=94%) for all-grade adverse events and 35·9% (29·5-42·9; I2=92%) for grade 3 or higher adverse events; and in the radiotherapy combination was 89·4% (69·0-96·9; I2=74%) for all-grade adverse events and 12·4% (4·4-30·6; I2=73%) for grade 3 or higher adverse events. For these four combination therapies, the most common all-grade adverse events were anaemia (45.4% [95% CI 32·4-59·1]), fatigue (34·3% [27·5-41·9]), fatigue (26·4% [19·2-35·2]), and dysphagia (30·0% [18·7-44·5]), respectively, and the most common grade 3 or higher adverse events were neutropenia (19·6% [13·5-27·7]), hypertension (9·3% [5·7-14·9]), lipase increased (7·2% [5·2-9·9]), and lymphopenia (10·3% [4·5-21·8]). All included randomised controlled trials had a low risk of bias. INTERPRETATION: Our study provides comprehensive data on treatment-related adverse events of different PD-1 or PD-L1 inhibitor-based combination therapies. Our results provide an essential reference of toxicity profiles of PD-1 or PD-L1 inhibitor-based combination therapies for clinicians in routine practice of cancer care. FUNDING: National Key Research and Development Programme, National Natural Science Foundation of China key program, National Natural Science Foundation of China general program, Chinese Academy of Medical Sciences Initiative for Innovative Medicine, Beijing Municipal Science and Technology Commission, Non-profit Central Research Institute Fund.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos como Assunto , Terapia Combinada/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Humanos , Incidência
6.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
7.
Oncology ; 99(9): 562-570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237736

RESUMO

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida
8.
Oncoimmunology ; 10(1): 1933332, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34262797

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy characterized by a poor prognosis. The treatment efficacy of immune checkpoint inhibitors (ICIs) also varies widely in advanced ccRCC. We aim to construct a robust gene signature to improve the prognostic discrimination and prediction of ICIs for ccRCC patients. In this study, adopting differentially expressed genes from seven ccRCC datasets in GEO (Gene Expression Omnibus), a novel signature (FOXM1&TOP2A) was constructed in TCGA (The Cancer Genome Atlas) database by LASSO and Cox regression. Survival and time-dependent ROC analysis revealed the strong predictive ability of our signature in discovery set, two online validation sets and one tissue microarray (TMA) from our institution. High-risk group based on the signature comprises more high-grade (G3&G4) and advanced pathologic stage (stageIII/IV) tumors and presents hyperactivation of cell cycle process according to the functional analysis. Meanwhile, high-risk tumors demonstrate an immunosuppressive phenotype with more infiltrations of regulatory T cells (Tregs), macrophages and high expressions of genes negatively regulating anti-tumor immunity. Low-risk tumors have an improved response to anti-PD-1 therapy and the predictive ability of our signature is better than other recognized biomarkers in ccRCC. A nomogram containing this signature showed a high predictive accuracy with AUCs of 0.90 and 0.84 at 3 and 5 years. Overall, this robust signature could predict prognosis, evaluate immune microenvironment and response to anti-PD-1 therapy in ccRCC, which is very promising in clinical promotion.


Assuntos
Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral
9.
Nat Commun ; 12(1): 4172, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234141

RESUMO

Cell-free DNA (cfDNA) is attractive for many applications, including detecting cancer, identifying the tissue of origin, and monitoring. A fundamental task underlying these applications is SNV calling from cfDNA, which is hindered by the very low tumor content. Thus sensitive and accurate detection of low-frequency mutations (<5%) remains challenging for existing SNV callers. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this challenge. Furthermore, by leveraging cfDNA's comprehensive coverage of tumor clonal landscape, cfSNV can profile mutations in subclones. In both simulated and real patient data, cfSNV outperforms existing tools in sensitivity while maintaining high precision. cfSNV enhances the clinical utilities of cfDNA by improving mutation detection performance in medium-depth sequencing data, therefore making Whole-Exome Sequencing a viable option. As an example, we demonstrate that the tumor mutation profile from cfDNA WES data can provide an effective biomarker to predict immunotherapy outcomes.


Assuntos
DNA Tumoral Circulante/genética , Análise Mutacional de DNA/métodos , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias/genética , Sequenciamento Completo do Exoma/métodos , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biópsia , DNA Tumoral Circulante/sangue , Simulação por Computador , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Sensibilidade e Especificidade
10.
Life Sci ; 282: 119813, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34256042

RESUMO

Immune checkpoint blockade has displayed substantial anti-tumor resistance in a variety of forms of cancer, but the fundamental regulation role remains unclear, and several questions continue to be addressed. PD-1/PD-L1 has been recognized as an anti-cancer drug target for several years, and through targeting the PD-1/PD-L1 signaling pathway, many monoclonal antibodies have thus far produced promising results in cancer therapy. The discovery of small-molecule inhibitors focused on the PD-1/PD-L1 signaling pathway is steadily reviving over decades, owing to the intrinsic shortcomings of the antibodies. PD-1 function and its PD-L1 or PD-L2 ligands are essential for the activation, proliferation, and cytotoxic secretion of T-cells in cancer to degenerate anti-tumor immune response. The axis PD-1/PD-L1 is important for the immune escape of cancer which has an immense impact on cancer treatment. In this review, we summarize the function of PD-1 and PD-L1 in cancer and aiming to enhance cancer therapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Antígeno B7-H1/imunologia , Humanos , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
11.
Medicine (Baltimore) ; 100(28): e26649, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34260566

RESUMO

BACKGROUND: The method to evaluate the efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors has become a big concern for researchers with its widely application. Pseudoprogressive disease (PPD) makes this process more difficult, which means that the tumor progressed at the initial evaluation, but re-evaluation after continued treatment suggested that the treatment was effective. However, PPD has not attracted enough attention of clinical doctors. This article is to systematically evaluate the incidence of PPD associated with PD-1/PD-L1 inhibitors with meta-analysis, to provide guidance for the recognition and management of PPD. METHODS: The databases of PubMed, EMBase, Cochrane Library were retrieved from the earliest collection date of the databases until Dec 5, 2019. The search terms of "pseudoprogressive disease, anti-PD-1, anti-PD-L1, PD-1/PD-L1 inhibitor, etc" were used for logistic combination search. Published studies on PPD caused by PD-1/PD-L1 inhibitors were included. Meta-analysis was performed with Stata 15.1. Subgroup analysis was performed according to the study population, tumor type, and evaluation criteria for efficacy. RESULTS: Seven researches, including 1458 patients were taken into the study. Meta-analysis showed that the overall incidence of PPD was 3.70% (95% confidence interval [CI]: 2.70%, 4.90%). Subgroup analysis showed that the incidence of PPD was 3.30% (95% CI: 1.90%, 5.90%) in non-small cell lung cancer patients and 5.10% (95% CI: 2.30%, 11.6%) in melanoma patients. There was no statistically significant difference between East and West populations and among various efficacy evaluation criteria. CONCLUSION: The incidence of PPD related to PD-1/PD-L1 inhibitors is not high, but the evaluation criteria has not yet been unified. Close monitoring, careful identification and proper application should be carried out in the clinic, and full management of the treatment with PD-1/PD-L1 inhibitors should be well done.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Carga Tumoral
12.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066087

RESUMO

Immune evasion is a key strategy adopted by tumor cells to escape the immune system while promoting their survival and metastatic spreading. Indeed, several mechanisms have been developed by tumors to inhibit immune responses. PD-1 is a cell surface inhibitory receptor, which plays a major physiological role in the maintenance of peripheral tolerance. In pathological conditions, activation of the PD-1/PD-Ls signaling pathway may block immune cell activation, a mechanism exploited by tumor cells to evade the antitumor immune control. Targeting the PD-1/PD-L1 axis has represented a major breakthrough in cancer treatment. Indeed, the success of PD-1 blockade immunotherapies represents an unprecedented success in the treatment of different cancer types. To improve the therapeutic efficacy, a deeper understanding of the mechanisms regulating PD-1 expression and signaling in the tumor context is required. We provide an overview of the current knowledge of PD-1 expression on both tumor-infiltrating T and NK cells, summarizing the recent evidence on the stimuli regulating its expression. We also highlight perspectives and limitations of the role of PD-L1 expression as a predictive marker, discuss well-established and novel potential approaches to improve patient selection and clinical outcome and summarize current indications for anti-PD1/PD-L1 immunotherapy.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Humanos , Neoplasias/fisiopatologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Evasão Tumoral
13.
Nat Commun ; 12(1): 3414, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099731

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Lactamas Macrocíclicas/farmacologia , Neutrófilos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Lactamas Macrocíclicas/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
14.
Nat Immunol ; 22(7): 851-864, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099918

RESUMO

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.


Assuntos
Anticorpos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-33/farmacologia , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
15.
Medicine (Baltimore) ; 100(25): e26471, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160456

RESUMO

RATIONALE: Advanced hepatocellular carcinoma (HCC) remains a deadly disease in part due to decades of limited therapeutic options. With recent advances in our understanding of the tumor biology, several promising treatment strategies involving targeted and immunotherapies have emerged. However, enhancing their modest efficacy in HCC and other gastrointestinal malignancies is essential to improving survival. PATIENT CONCERNS: A man in his late 50s with a history of type 2 diabetes mellitus and morbid obesity initially presented with progressive abdominal pain and anorexia prompting an abdominal computed tomography scan that revealed a large solitary liver mass with extensive local involvement. DIAGNOSES: Although there were features consistent with a primary gastric tumor on subsequent endoscopic evaluation leading to early diagnostic uncertainty, his clinical picture, including a dominant liver mass, immunohistochemical staining profile, and significantly elevated alpha fetoprotein ultimately favored HCC. INTERVENTIONS: The patient received palliative systemic therapy with infusional fluorouracil for a presumed gastric primary, however restaging scans after 3 cycles demonstrated disease progression. The consensus from a multidisciplinary discussion was that his pathology was more consistent with primary HCC. He was subsequently started on nivolumab with a partial response, although after 5 months, he progressed prompting initiation of second-line atezolizumab and bevacizumab with a favorable response. OUTCOMES: The addition of atezolizumab and bevacizumab led to a sustained biochemical and radiographic response that appeared to overcome the resistance to nivolumab monotherapy. Aside from several mild immune-related adverse effects, his quality of life has greatly improved and he has tolerated treatment well to date. LESSONS: Our findings suggest that vascular endothelial growth factor inhibition can overcome resistance to checkpoint inhibition in advanced HCC by resulting in a unique synergy that has never before been described in patients. The biological rationale for this response is likely attributable to the immunomodulatory effects of antiangiogenic agents, promoting an immunostimulatory microenvironment that can be exploited by immune checkpoint inhibitors for more effective antitumor activity. Given the considerable benefit patients may derive following progression on first-line treatment, it is important to consider this strategic combination of therapies which can ultimately lead to improved patient outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
16.
Science ; 372(6547)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34112666

RESUMO

Next-generation tissue-based biomarkers for immunotherapy will likely include the simultaneous analysis of multiple cell types and their spatial interactions, as well as distinct expression patterns of immunoregulatory molecules. Here, we introduce a comprehensive platform for multispectral imaging and mapping of multiple parameters in tumor tissue sections with high-fidelity single-cell resolution. Image analysis and data handling components were drawn from the field of astronomy. Using this "AstroPath" whole-slide platform and only six markers, we identified key features in pretreatment melanoma specimens that predicted response to anti-programmed cell death-1 (PD-1)-based therapy, including CD163+PD-L1- myeloid cells and CD8+FoxP3+PD-1low/mid T cells. These features were combined to stratify long-term survival after anti-PD-1 blockade. This signature was validated in an independent cohort of patients with melanoma from a different institution.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/análise , Imunofluorescência , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígeno B7-H1/análise , Antígenos CD8/análise , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Proteínas de Checkpoint Imunológico/análise , Macrófagos/química , Masculino , Melanoma/química , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/análise , Intervalo Livre de Progressão , Receptores de Superfície Celular/análise , Fatores de Transcrição SOXE/análise , Análise de Célula Única , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Microambiente Tumoral
17.
Aging (Albany NY) ; 13(12): 16656-16666, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34170847

RESUMO

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Patches were implanted to the rat IVC and harvested on day 14 and analyzed. Immunohistochemical analysis showed PD-1-positive cells in the neointima in the human samples. There was high protein expression of PD-1 in the neointima in the rat IVC venoplasty model. PD-1 antibody injection can significantly decrease neointimal thickness (p < 0.0001). PD-1 antibody or BMS-1 was successfully conjugated to the decellularized rat thoracic artery patch by hyaluronic acid with altered morphology and reduced the water contact angle (WCA). Patches coated with humanized PD-1 antibody or BMS-1 both can also decrease neointimal hyperplasia and inflammatory cells infiltration. PD-1-positive cells are present in venous neointima in both human and rat samples. Inhibition of the PD-1 pathway may be a promising therapeutic strategy to inhibit venous neointimal hyperplasia.


Assuntos
Neointima/metabolismo , Neointima/patologia , Receptor de Morte Celular Programada 1/metabolismo , Veias/metabolismo , Veias/patologia , Animais , Humanos , Hiperplasia/metabolismo , Injeções Intraperitoneais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Ratos , Bibliotecas de Moléculas Pequenas/farmacologia , Água
18.
Cancer Treat Rev ; 99: 102242, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34153830

RESUMO

BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Oncoimmunology ; 10(1): 1933808, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34188973

RESUMO

Checkpoint blockade therapy is effective against many cancers; however, new targets need to be identified to treat patients who do not respond to current treatment or demonstrate immune escape. Here, we showed that blocking the inhibitory receptor Killer cell lectin-like receptor G1 (KLRG1) enhances anti-tumor immunity mediated by NK cells and CD8+ T cells. We found that loss of KLRG1 signaling alone significantly decreased melanoma and breast cancer tumor growth in the lungs of mice. In addition, we demonstrated that KLRG1 blockade can synergize with PD-1 checkpoint therapy to increase the therapeutic efficacy compared to either treatment alone. This effect was even observed with tumors that do not respond to PD-1 checkpoint therapy. Double blockade therapy led to significantly decreased tumor size, increased frequency and activation of CD8+ T cells, and increased NK cell frequency and maturation in the tumor microenvironment. These findings demonstrate that KLRG1 is a novel checkpoint inhibitor target that affects NK and T cell anti-tumor immunity, both alone and in conjunction with established immunotherapies.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias , Receptor de Morte Celular Programada 1 , Animais , Linfócitos T CD8-Positivos , Humanos , Imunoterapia , Células Matadoras Naturais , Lectinas Tipo C/antagonistas & inibidores , Camundongos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptores Imunológicos/antagonistas & inibidores , Microambiente Tumoral
20.
Hematol Oncol ; 39 Suppl 1: 39-45, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105815

RESUMO

The treatment of classical Hodgkin lymphoma in young patients is one of the success stories of modern medicine. The use of risk- and response-adapted approaches to guide treatment decisions has led to impressive cure rates while reducing the long-term toxicity associated with more intensive therapies. Tissue biomarkers have not yet proven more effective than clinical characteristics for risk stratification of patients at presentation, but functional imaging features such as metabolic tumor volume may be used to predict response, if early observations can be validated. The success of treatment in younger patients has unfortunately not been mirrored in those over 60, where complex decision-making is often required, with a paucity of data from clinical trials. The use of PD1 blocking antibodies and brentuximab vedotin in this cohort, either alone or in combination with chemotherapy, may provide attractive options. The incorporation of frailty assessment, quality-of-life outcomes, and specialist geriatric input is also important to ensure the best outcomes for this diverse group.


Assuntos
Biomarcadores Tumorais , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Neoplasias , Medicina de Precisão , Receptor de Morte Celular Programada 1 , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
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