RESUMO
Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6+ ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis.
Assuntos
Movimento Celular , Fibrose , Rim , Linfócitos , Receptor de Morte Celular Programada 1 , Receptores CXCR6 , Receptores de Interleucina , Transdução de Sinais , Animais , Fibrose/imunologia , Camundongos , Receptores CXCR6/metabolismo , Receptores CXCR6/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais/imunologia , Movimento Celular/imunologia , Humanos , Rim/patologia , Rim/imunologia , Rim/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina/imunologia , Camundongos Endogâmicos C57BL , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Imunidade Inata/imunologia , Camundongos Knockout , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/imunologia , Intestinos/patologiaRESUMO
Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases, including oral cancer. Cancer cells usually escape from the immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα, in the tumor microenvironment of oral squamous cell carcinoma (OSCC), performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating to seven immune-related factors and several clinicopathological statuses. However, the immune checkpoint-related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that the keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference in tumor immunity in the originating epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC, might be different in the originating epithelium, keratinized or non-keratinized.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Antígeno B7-H1 , Antígeno CD47 , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Epitélio , Microambiente TumoralRESUMO
Immunotherapy related adverse events are commonly seen with immune check point inhibitors therapy. We report the case of a 40-year-old female diagnosed with stage IVB endometroid grade III endometrial cancer, on pembrolizumab immunotherapy, an anti-programmed-death-receptor-1 (PD-1) antibody. Patient was referred for 18F-FDG PET/CT for restaging. 18F-FDG PET/CT demonstrated diffuse increased FDG uptake throughout the body of the pancreas associated with fat stranding in the peripancreatic region, suggestive of pembrolizumab-induced pancreatitis. The diagnosis was confirmed by elevated amylase and lipase levels. immune-related adverse events (irAE) are frequently identified on 18F-FDG PET-CT, which may lead to early diagnosis, close clinical follow-up, and appropriate clinical management of immune-related adverse events.
Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Fluordesoxiglucose F18 , Pancreatite , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Feminino , Humanos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Pancreatite/imunologia , Pancreatite/induzido quimicamente , Pancreatite/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
AIM: The use of immune checkpoint inhibitors (ICIs) has increased remarkably, and immune-related adverse events (irAEs) have also increased. This study aimed to identify factors associated with immune-related liver injury (irLI), and the relationship between the grades of irLI and overall survival (OS) in patients treated with ICIs. METHODS: A total of 571 patients who had been treated for advanced malignancies with ICIs between January 2015 and March 2022 were retrospectively recruited. The presence of liver injury was determined by the aspartate aminotransferase and alanine aminotransferase elevation. The irLI grading was based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 50 (8.8%) patients had grade ≥2 irLI and 24 (4.2%) had grade ≥3 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 agents and baseline grade 1 aspartate aminotransferase/alanine aminotransferase elevation were independent predictive factors of grade ≥2 irLI. Treatment with anti-cytotoxic T-lymphocyte-associated protein-4 was the only independent predictive factor of grade ≥3 irLI. The median OS for patients who experienced any irAEs was significantly longer than of those without irAEs (hazard ratio 0.503, 95% CI 0.398-0.636, p < 0.001). The median OS in patients with grade ≥2 irLI was significantly longer (HR 0.570, 95% CI 0.387-0.838, p = 0.022). There was no significant difference between the median OS in patients with grade ≥3 irLI and the others (p = 0.11). CONCLUSION: The incidence of irLI was significantly higher in patients treated with anti-cytotoxic T-lymphocyte-associated protein-4 agents. Even in patients with pre-existing grade 1 aspartate aminotransferase/alanine aminotransferase elevation, appropriate follow-up and control of the irLI can improve the prognosis.
RESUMO
OPINION STATEMENT: Strategies using immune checkpoint inhibitors (ICI), which can enhance antitumor immune responses, have revolutionized the lung cancer therapeutic landscape. The ICI mechanism of action involves the blockade of regulatory cell surface molecules using antibodies against the Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) (ipilimumab, tremelimumab); the programmed death receptor-1 (PD-1; nivolumab, pembrolizumab); or the PD ligand-1 (PD-L1; atezolizumab, durvalumab). Notably, anti-PD-1 demonstrated long-term survival benefits, durable objective responses, and a manageable safety profile in patients with non-small cell lung cancer (NSCLC). The combination of anti-PD1 or anti-PD-L1 and platinum chemotherapy achieved better survival outcomes than chemotherapy alone, which was observed irrespective of PD-L1 expression on cancer cells. Although promising results have been reported from large clinical trials, especially for patients with high PD-L1 expression, the optimal treatment approach for patients with PD-L1-negative NSCLC has yet to be defined. We propose a guide for clinicians in the therapeutic decision-making process based on the latest data available about treatments, prognostic factors, predictive biomarkers, and real-world evidence in PD-L1-negative NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Antígeno B7-H1 , Nivolumabe/uso terapêutico , IpilimumabRESUMO
INTRODUCTION: Immunotherapy has become a standard treatment for lung cancer; the objective of this study was to evaluate the effectiveness, safety of pembrolizumab monotherapy in patients with advanced or metastatic non-small-cell lung cancer used in real-world clinical practice. MATERIAL AND METHODS: Retrospective observational study of every patient treated with pembrolizumab in our centre from January 2017 to June 2019. Outcomes collected: sex, age, Eastern Cooperative Oncology Group, programmed death receptor 1 level, previous metastatic line therapies, adverse events and smoking status. RESULTS: A total of 62 patients were reviewed. The median age was 62.34 ± 10.62 years, 48 (77.41%) were men and 91.93% of patients had Eastern Cooperative Oncology Group 0. The median dose administered was 170.5â mg (108 - 240â mg) and the median follow-up was 3 months (range: 1 - 38). A median of four cycles of pembrolizumab (range: 1 - 56) were administered as monotherapy. The reason for treatment discontinuation was mainly due to disease progression in 38.70% of patients or death in 30.64%. As first-line pembrolizumab monotherapy, median progression-free survival was 7.7 months (95% CI: 3.66 - 11.73) (N = 33). With respect to patients who were treated in second-third-line treatment, median progression-free survival was 3.5 months (95% CI: 2.40 - 4.59) (N=29). As to overall survival, pembrolizumab-treated patients as first-line treatment reached 19 months median OG (95% CI: 13.36 - 24.63) (N = 33) and those treated in second-third-line treatment got 11 months (95% CI: 3.4 - 18.5). A total of 64.51% of patients presented some adverse events to pembrolizumab however, only, 9.38% of them were grade 3. CONCLUSION: Pembrolizumab represents an effective and feasible alternative in terms of progression-free survival. It is a well-tolerated treatment option.
Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Intervalo Livre de ProgressãoRESUMO
In recent years, immune checkpoint blockade (ICB) therapy has become an important treatment strategy for gastrointestinal tumors, however, it only benefits about 1/3 of patients. Since the microbiome has been shown to play an important role in the human body for a long time, a growing number of studies are focusing on its relationship to ICB therapy in cancer, specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors (ICIs) therapy in patients. On this basis, probiotic interventions, fecal microbiota transplantation (FMT), dietary interventions, and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention. This article discusses the four aspects of the microbiome, ICB, combined treatment of gastrointestinal tumors, and regulation of gut microbiome. Particularly, the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects (irAEs).
RESUMO
Tislelizumab is an anti-programmed death receptor 1 (PD-1) monoclonal immunoglobulin G 4 antibody developed by BeiGene. The structure of tislelizumab has been modified to maximally inhibit the binding of PD-1 to programmed death ligand 1 (PD-L1) and minimize the binding of tislelizumab to Fcγ receptors. In clinical studies, tislelizumab has shown preliminary anti-tumor effects in various solid tumors, such as Hodgkin's lymphoma, urothelial carcinoma, lung cancer, gastric and esophageal cancer, liver cancer, nasopharyngeal carcinoma, colorectal cancer, and microsatellite instability-high/mismatch repair-deficient tumors. In addition, it also showed new promise in solid tumor treatment in combination with ociperlimab. Due to its satisfactory anti-tumor effects, tislelizumab has received approvals in China for the treatment of classical Hodgkin's lymphoma, urothelial carcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and hepatocellular carcinoma, and it is now under investigation for a new indication in microsatellite instability-high/mismatch repair-deficient tumors. Moreover, it has been granted orphan designations in hepatocellular carcinoma, esophageal cancer, and gastric cancer, including cancer of the gastroesophageal junction, by the US Food and Drug Administration. Tislelizumab has an acceptable safety profile; the most common adverse effects include fatigue, anemia, and decreased neutrophil count, while the most fatal events have been related to respiratory infection or failure, and hepatic injury. Tislelizumab has an economic advantage compared with other well-studied PD-1/PD-L1 inhibitors; thus, the introduction of it could provide clinical oncologists with an effective weapon against tumors and may alleviate the burden of cancer patients.
Assuntos
Carcinoma Hepatocelular , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células de Transição , Neoplasias Esofágicas , Doença de Hodgkin , Neoplasias Pulmonares , Neoplasias Gástricas , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1 , Neoplasias Esofágicas/tratamento farmacológico , Doença de Hodgkin/terapia , Humanos , Instabilidade de Microssatélites , Receptor de Morte Celular Programada 1 , Receptores de Morte Celular , Neoplasias Gástricas/tratamento farmacológicoRESUMO
Primary liver cancer, mainly hepatocellular carcinoma (HCC), is the sixth most diagnosed cancer and third leading cause of cancer-related death globally. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs) have made great progress in the systemic treatment of HCC. However, anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and CheckMate 459 trials. It is urgent to understand the immunological rationale and explore novel ways to improve the efficacy of immunotherapy. The combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), monoclonal antibodies, or local therapy, has been demonstrated to improve overall response rate and survival. In addition, modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies. In this review, we summarized the latest findings in the immune microenvironment, the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs, as well as other kinds of immune treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Fatores Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Microambiente TumoralRESUMO
Objective: To investigate the effect of programmed death receptor (PD)-1 antibody therapy in patients with hepatitis B-associated liver cancer. Methods: Data of 29 chronically infected HBV patients with liver cancer who received PD-1 antibody combined with tyrosine kinase inhibitor in the Department of Infectious Diseases of the Fifth Medical Center of PLA General Hospital from March 2020 to January 2021 were selected. At the same time, all of the above-mentioned hepatitis B virus (HBV) patients were treated with nucleos(t)ide analogues. Patients clinical diagnostic data, laboratory test results, tumor response and the incidence of adverse reactions were collected retrospectively to understand the overall safety, therapeutic anti-tumor effect, HBV changes condition and the correlation between HBV changes and anti-tumor PD-1 antibody efficacy, high viral load treatment condition, and HBV reactivation safety issues. Statistical analysis was performed by non-parametric rank sum test. Results: Therapeutic anti-tumor effect and safety profile were good in patients. The complete remission rate was reached 27.6%. Adverse reactions were mostly mild, and the incidence of serious adverse reactions was low. After 12 weeks of follow-up, HBV DNA and hepatitis B surface antigen (HBsAg) was quantitatively decreased (P < 0.05). HBV DNA and HBsAg were decreased more significantly in patients with progressive disease (PD), stable disease (SD) and partial response (PR) (P < 0.05). Five patients with HBV DNA ≥ 10(4) IU/ml had responded well to the tumor treatment without serious adverse reactions. One patient had a slight increase in HBV DNA and alanine aminotransferase, while there was no HBV reactivation and correlated liver damage. Conclusion: Patients with HBV-associated liver cancer who received combined therapy have good anti-tumor efficacy and safety profile. PD-1 treatment has a certain effect on HBV. Compared with non-responders, patients with tumor response have better antiviral treatment efficacy. The safety of treatment in patients with high viral load is manageable, and there are no safety issues related to HBV reactivation.
Assuntos
Hepatite B , Neoplasias Hepáticas , Antivirais/uso terapêutico , DNA Viral , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Receptores de Morte Celular , Estudos Retrospectivos , Ativação ViralRESUMO
INTRODUCTION: The landscape for the treatment of metastatic melanoma has been revolutionized with the introduction immune checkpoint inhibitors. Immune checkpoint inhibitors have now become the standard of care for the treatment of cancers. These immune agents including programmed death receptor-1 inhibitors, programmed death-ligand 1 inhibitors and cytotoxic T-lymphocyte antigen-4 inhibitors have shown promising results but have been associated with numerous immune-related complications. Pembrolizumab, a programmed death receptor-1 inhibitor, has been associated with a number of immune-related adverse events affecting multiple organ systems including integument, ocular, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, and musculoskeletal system. CASE REPORT: We present a case of an 88-year-old Caucasian male with metastatic melanoma of the face with metastasis to the right fifth cranial nerve and into the right cavernous sinus. He underwent resection of the melanoma and was placed on pembrolizumab at 2 mg/kg every three weeks. Interestingly, 24 months on pembrolizumab therapy, he developed corneal erosions, oral and genital ulcerations. MANAGEMENT AND OUTCOME: Patient completed his 24 months of pembrolizumab and was started on prednisone and colchicine with improvement in his symptoms. At his follow-up eight months, he had recurrence of an oral ulcer. DISCUSSION: Here we present a rare case of an elderly male on pembrolizumab who suffered from corneal erosions, oral and genital ulcers, a syndrome similar to Behcet's disease. Given that pembrolizumab and other immune checkpoint inhibitors are being utilized in the treatment of cancers, physicians should be aware of the wide range immune-related adverse events including the possible Behcet's-like syndrome presentation.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Síndrome de Behçet/induzido quimicamente , Síndrome de Behçet/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso de 80 Anos ou mais , Síndrome de Behçet/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Humanos , MasculinoRESUMO
Targeting the interaction interface is an effective strategy to obtain programmed death receptor 1 (PD-1)/PD-1 ligand 1 (PD-L1) nanobody blockers. To validate this strategy, the interaction interface between PD-1 and the PD-L1 extracellular domain were analyzed using Cn3D 4.1. The peptide PD-1125-136 located at the interface of PD-1 was selected as the antigen to screen nanobodies from a humanized nanobody phage display library. Six different nanobodies were screened, with molecular weights of 12 â¼ 13 kDa, excluding a single basic protein. The nanobody with the longest CDR3 region, termed PD-1-Nb-B20, was selected for further analysis. For mass production, the C-terminal His6-tagged nanobody coding sequence was optimized and cloned into pET-21b for over-expression under the T7 promoter in Escherichia coli BL21 (DE3). PD-1-Nb-B20 was expressed and pancreatic adenocarcinoma cells BxPC-3 over-expressing PD-L1 were selected for nanobody competitive inhibition assays. The purified nanobodies significantly inhibited PD-1 binding to the surface of target cells, indicating their ability to block the PD-1/PD-L1 interaction.
Assuntos
Antineoplásicos Imunológicos , Antígeno B7-H1/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Pancreáticas/imunologia , Receptor de Morte Celular Programada 1/imunologia , Anticorpos de Domínio Único , Células A549 , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/isolamento & purificação , Células HeLa , Humanos , Anticorpos de Domínio Único/química , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/isolamento & purificação , Neoplasias PancreáticasRESUMO
Immunotherapy may be an effective way to prevent postoperative recurrence of renal cell carcinoma. Streptavidin-interleukin-2 (SA-IL-2) surface-modified tumor cell vaccine developed through our protein-anchor technology could induce specific antitumor T-cell responses, but this immunotherapy cannot completely eradicate the tumor. These effector T cells highly expressed programmed death receptor-1 (PD-1), and the expression of programmed death ligand-1 (PD-L1) in the tumor environment also was upregulated after SA-IL-2-modified vaccine therapy. PD-1/PD-L1 interaction promotes tumor immune evasion. Adding PD-1 blockade to SA-IL-2-modified vaccine therapy increased the number of CD4+ , CD8+ and CD8+ interferon-γ+ but not CD4+ Foxp3+ T cells. PD-1 blockade could rescue the activity of tumor-specific T lymphocytes induced by the SA-IL-2-modified vaccine. Combination therapy delayed tumor growth and protected mice against a second Renca cells but not melanoma cells challenge. Taken together, PD-1 blockade could reverse immune evasion in the treatment with SA-IL-2-modified vaccine, and eventually induce a stronger specific antitumor immune response against renal cell carcinoma.
Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma de Células Renais/terapia , Imunoterapia/métodos , Interleucina-2/imunologia , Neoplasias Renais/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Terapia Combinada , Interferon gama/imunologia , Interferon gama/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismoRESUMO
The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single-arm trials, IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%-32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%-33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD-L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD-1/PD-L1. Two ongoing trials (IMvigor130 and KEYNOTE-361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin-ineligible patients. Both drugs are now indicated for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD-L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum-based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. IMPLICATIONS FOR PRACTICE: The accelerated approvals of atezolizumab and pembrolizumab for cisplatin-ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single-arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non-cisplatin-containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin-ineligible patients. Both are now indicated either for patients not eligible for any platinum-containing chemotherapy or not eligible for cisplatin-containing chemotherapy and whose tumors have high expression of PD-L1.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Cisplatino , Aprovação de Drogas , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Neoplasias Urológicas/patologiaRESUMO
PD-1 is highly expressed on tumor-infiltrated antigen-specific T cells and limit the antitumor function. Blocking of PD-1/PD-L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE-A3-specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE-A3-specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE-A3-specific CD8+ T cells could lyse HLA-A2+ /MAGE-A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD-1 was highly expressed on dysfunctional antigen-specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid-derived suppressor cells (MDSCs) derived-TGF-ß mediated PD-1high expression on CD8+ T cells, which led to be resistance to PD-1/PD-L1 blockade in TME. Dual PD-1/PD-L1 and TGF-ß signaling pathway blockades synergistically restored the function and antitumor ability of antigen-specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE-A3-specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs-derived TGF-ß increased PD-1 expression on T cells and decreased the sensitivity to PD-1/PD-L1 blockade. Combining T cell-based therapy with dual PD-1/PD-L1 and TGF-ß signaling pathway blockade could be considered a promising strategy for cancer treatment.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/terapia , Proteínas de Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Epitopos de Linfócito T , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/imunologia , Antígeno HLA-A2/imunologia , Humanos , Camundongos , Receptor de Morte Celular Programada 1/imunologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Objective: To explore the expression and distribution of programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3) in breast cancer microenvironment and analyze the their correlation with the clinicopathological features. Methods: The specimens of tumor tissue and adjacent tissues from 30 patients with infiltrative breast cancer who were diagnosed as breast cancer from June 2016 to May 2017 in The First Hospital of Jiaxing were collected, and the specimen were divided into two parts along the center. After embedding and cryosectioning, the expression and distribution of PD-1 and TIM-3 protein in tumor tissues were observed by immunofluorescence staining. Another part of the specimen was cut and digested, and non-continuous density gradient centrifugation was used to extract tumor-infiltrating lymphocytes (TILs), real-time quantitative PCR (qRT-PCR) was used to detect the mRNA expression of PD-1 and TIM-3 in TILs. Meanwhile, the protein expression was determined by Western blotting. The relationship between the expression of PD-1 and TIM-3 and pathological parameters of breast cancer was analyzed with correlation analysis. Results: Immunofluorescence results showed that more PD-1 and TIM-3 positive cells were observed in the tumor tissues compared with the tumor-adjacent tissues. The qRT-PCR showed that the expression of PD-1 and TIM-3 mRNA in TILs were both significantly higher than those in paracancerous tissues (3.09±0.38 vs 1.26±0.23, 3.42±0.31 vs 1.57±0.29, t=4.16, 4.37, both P<0.05). At the protein level, the expression of PD-1 and TIM-3 in tumor tissue lymphocytes(0.66±0.08, 0.80±0.11) was significantly higher than those in cancerous tissues(0.10±0.01, 0.26±0.02) (t=6.79, 4.57, both P<0.05). There were significant differences in the expression of PD-1, TIM-3 mRNA in the TILs between the different tumor histological grades, tumor sizes, lymph node metastasis (t=2.22-2.99, all P<0.05). Correlation analysis showed that there was a significant positive correlation between the expression of PD-1 and TIM-3 in tumor tissues (r=0.616, P<0.01). Conclusions: In the breast cancer microenvironment, PD-1, TIM-3-mediated signaling pathway plays an important role in the occurrence and development of breast cancer, it provides a new basis for the combination therapy of breast cancer.
Assuntos
Microambiente Tumoral , Linfócitos T CD8-Positivos , Humanos , Imunoglobulinas , Mucina-3 , Receptor de Morte Celular Programada 1RESUMO
Programmed cell death 1 ligand 1 (PD-L1) is a promising therapeutic target for cancer immunotherapy. However, the correlation between PD-L1 and breast cancer survival remains unclear. Here, we present the first meta-analysis to investigate the prognostic value of PD-L1 in breast cancer. We searched Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases for relevant studies evaluating PD-L1 expression and breast cancer survival. Fixed- and random-effect meta-analyses were conducted based on heterogeneity of included studies. Publication bias was evaluated by funnel plot and Begg's test. Overall, nine relevant studies with 8583 patients were included. PD-L1 overexpression was found in 25.8% of breast cancer patients. PD-L1 (+) associated with several high-risk prognostic indicators, such as ductal cancer (p = 0.037), high tumor grade (p = 0.000), ER negativity (p = 0.000), PR negativity (p = 0.000), HER2 positivity (p = 0.001) and aggressive molecular subtypes (HER2-rich and Basal-like p = 0.000). PD-L1 overexpression had no significant impact on metastasis-free survival (HR 0.924, 95% CI = 0.747-1.141, p = 0.462), disease-free survival (HR 1.122, 95% CI = 0.878-1.434, p = 0.357) and overall specific survival (HR 0.837, 95% CI = 0.640-1.093, p = 0.191), but significantly correlated with shortened overall survival (HR 1.573, 95% CI = 1.010-2.451, p = 0.045). PD-L1 overexpression in breast cancer associates with multiple clinicopathological parameters that indicated poor outcome, and may increase the risk for mortality. Further standardization of PD-L1 assessment assay and well-controlled clinical trials are warranted to clarify its prognostic and therapeutic value.
Assuntos
Biomarcadores/metabolismo , Neoplasias da Mama/diagnóstico , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , PrognósticoRESUMO
BACKGROUND: Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. PATIENTS AND METHODS: Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. RESULTS: None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. CONCLUSIONS: In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.
Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/sangue , Coriocarcinoma/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Testiculares/patologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Humanos , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/mortalidade , Pesquisa Translacional Biomédica , Adulto JovemRESUMO
A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available.
Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Nivolumabe , Receptor de Morte Celular Programada 1/efeitos dos fármacos , Receptor de Morte Celular Programada 1/metabolismo , Controle de QualidadeRESUMO
Programmed death-ligand 1 (PD-L1) has become a crucial focus in cancer immunotherapy considering it is found in many different cells. Cancer cells enhance the suppressive impact of programmed death receptor 1 (PD-1) through elevating PD-L1 expression, which allows them to escape immune detection. Although there have been significant improvements, the effectiveness of anti-PD-1/PD-L1 treatment is still limited to a specific group of patients. An important advancement in cancer immunotherapy involves improving the PD-L1 protein degradation. This review thoroughly examined the processes by which PD-L1 breaks down, including the intracellular pathways of ubiquitination-proteasome and autophagy-lysosome. In addition, the analysis revealed changes that affect PD-L1 stability, such as phosphorylation and glycosylation. The significant consequences of these procedures on cancer immunotherapy and their potential role in innovative therapeutic approaches are emphasised. Our future efforts will focus on understanding new ways in which PD-L1 degradation is controlled and developing innovative treatments, such as proteolysis-targeting chimeras designed specifically to degrade PD-L1. It is crucial to have a thorough comprehension of these pathways in order to improve cancer immunotherapy strategies and hopefully improve therapeutic effectiveness.