RESUMO
BACKGROUND: Increasing hepatitis-related mortality has reignited interest to fulfill the World Health Organization's goal of viral hepatitis elimination by 2030. However, economic barriers have enabled only 28% of countries to implement countermeasures. Given the high disease burden among Asians, we aimed to present age, sex, disease activity and treatment-specific annual progression rates among Asian chronic hepatitis B (CHB) patients to inform health economic modeling efforts and cost-effective public health interventions. METHODS: We analyzed 18,056 CHB patients from 36 centers across the U.S. and seven countries/regions of Asia Pacific (9530 treated; 8526 untreated). We used Kaplan-Meier methods to estimate annual incidence of cirrhosis and hepatocellular carcinoma (HCC). Active disease was defined by meeting the APASL treatment guideline criteria. RESULTS: Over a median follow-up of 8.55 years, there were 1178 incidences of cirrhosis and 1212 incidences of HCC (297 without cirrhosis, 915 with cirrhosis). Among the 8526 untreated patients (7977 inactive, 549 active), the annual cirrhosis and HCC incidence ranged from 0.26% to 1.30% and 0.04% to 3.80% in inactive patients, and 0.55 to 4.05% and 0.19 to 6.03% in active patients, respectively. Of the 9530 treated patients, the annual HCC rates ranged 0.03-1.57% among noncirrhotic males and 2.57-6.93% among cirrhotic males, with lower rates for females. Generally, transition rates increased with age, male sex, the presence of fibrosis/cirrhosis, and active disease and/or antiviral treatment. CONCLUSION: Using data from a large and diverse real-world cohort of Asian CHB patients, the study provided detailed annual transition rates to inform practice, research and public health planning.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Cirrose Hepática , Neoplasias Hepáticas , Antivirais/uso terapêutico , Povo Asiático , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Feminino , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/epidemiologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , MasculinoRESUMO
In the tumor microenvironment, multiple inhibitory checkpoint receptors can suppress T-cell function, thereby enabling tumor immune evasion. Blockade of one of these checkpoint receptors, PD-1, with therapeutic antibodies has produced positive clinical responses in various cancers; however, the efficacy of this approach can be further improved. Simultaneously targeting multiple inhibitory checkpoint receptors has emerged as a promising therapeutic strategy. Here, we report the development and characterization of REGN3767, a fully human IgG4 antibody targeting LAG-3, another inhibitory receptor on T cells. REGN3767 binds human and monkey LAG-3 with high affinity and specificity and blocks the interaction of LAG-3 with its ligand, MHC class II. In an engineered T-cell/antigen-presenting cell bioassay, REGN3767 alone, or in combination with cemiplimab (REGN2810, human anti-PD-1 antibody), blocked inhibitory signaling to T cells mediated by hLAG-3/MHCII in the presence of PD-1/PD-L1. To test the in vivo activity of REGN3767 alone or in combination with cemiplimab, we generated human PD-1xLAG-3 knockin mice, in which the extracellular domains of mouse Pdcd1 and Lag3 were replaced with their human counterparts. In these humanized mice, treatment with cemiplimab and REGN3767 showed increased efficacy in a mouse tumor model and enhanced the secretion of proinflammatory cytokines by tumor-specific T cells. The favorable pharmacokinetics and toxicology of REGN3767 in nonhuman primates, together with enhancement of antitumor efficacy of anti-PD-1 antibody in preclinical tumor models, support its clinical development.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD/química , Antígenos CD/genética , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD/metabolismo , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Técnicas de Introdução de Genes , Haplorrinos , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Camundongos , Neoplasias/genética , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4(S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knock-in mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD-1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy. Mol Cancer Ther; 16(5); 861-70. ©2017 AACR.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/genética , Animais , Anticorpos Monoclonais Humanizados/imunologia , Linhagem Celular Tumoral , Técnicas de Introdução de Genes , Humanos , Imunoterapia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.
Assuntos
Testes de Carcinogenicidade/métodos , Carcinógenos/toxicidade , Testes de Mutagenicidade/métodos , Animais , Testes de Carcinogenicidade/normas , Carcinógenos/normas , Bases de Dados Factuais , Árvores de Decisões , Modelos Animais de Doenças , Estudos de Avaliação como Assunto , Feminino , Guias como Assunto , Humanos , Imunossupressores , Masculino , Camundongos , Camundongos Transgênicos , Testes de Mutagenicidade/normas , Neoplasias/induzido quimicamente , Ratos , Ratos Endogâmicos F344 , Fatores de Risco , Estatística como Assunto , Testes de Toxicidade CrônicaRESUMO
In the Eker rat model, inactivation of the Tuberous Sclerosis-2 (Tsc-2) tumor suppressor gene leads to high frequency of spontaneous renal cell carcinoma (RCC). By analogy to human RCC in which mutations in the von Hippel-Lindau (VHL) tumor suppressor gene result in accumulation of hypoxia-inducible factor alpha (HIFalpha) and up-regulation of vascular endothelial growth factor (VEGF), we investigated the regulation of HIF and its target gene VEGF in rat RCC resulting from Tsc-2 defects. To examine HIFalpha activity, a panel of rat renal epithelial cells were analyzed for expression of HIF1alpha and the homologous protein, HIF2alpha, under normoxic and hypoxic conditions. RCC-derived cell lines exhibited high basal levels of HIF activity as determined using hypoxia response element-luciferase reporter constructs. HIF2alpha was stabilized in RCC-derived cell lines and in five of six primary tumors compared with normal kidney, which was consistent with the high levels of hypoxia response element-reporter activity observed in the cell lines. Primary RCCs that developed in Eker rats were highly vascularized, which was similar to their human counterparts. Furthermore, reverse-transcriptase PCR and immunoblotting demonstrated that VEGF was abundantly expressed in both rat RCC cell lines and primary tumors. The 120-, 164-, and 188-amino-acid isoforms of VEGF were expressed at the RNA and protein levels in RCC-derived cell lines, although only a single band was observed in primary tumors. Taken together, these data suggest that RCC caused by loss of the Tsc-2 tumor suppressor gene (which retain wild-type Vhl) up-regulate VEGF via a HIF2alpha-mediated mechanism. Thus, loss of Tsc-2 and VHL tumor suppressor gene function appears to have similar consequences in Eker rats and humans respectively, identifying dysregulation of HIFalpha and VEGF expression as a common pathway for the development of RCC in different species and in tumors with different molecular etiologies.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Proteínas Repressoras/genética , Transativadores/biossíntese , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carcinoma de Células Renais/metabolismo , Fatores de Crescimento Endotelial/biossíntese , Fatores de Crescimento Endotelial/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Genes Supressores de Tumor , Subunidade alfa do Fator 1 Induzível por Hipóxia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Renais/metabolismo , Linfocinas/biossíntese , Linfocinas/genética , Ratos , Transativadores/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Ativação Transcricional , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Tuberin, the product of the tuberous sclerosis complex 2 tumor suppressor gene, is a phosphoprotein that negatively regulates phosphatidylinositol 3'-kinase signaling downstream of Akt. Several high stringency 14-3-3 binding sites that overlapped with Akt phosphorylation sites were identified in tuberin in silico. Recognition of tuberin by an alpha-14-3-3 binding site-specific antibody correlated with mitogen-induced phosphorylation of tuberin and recognition of tuberin by an alpha-Akt phosphorylation substrate antibody. Recognition of tuberin by both antibodies was blocked by inhibiting phosphatidylinositol 3'-kinase activity. Using a protein domain microarray, a tuberin peptide containing Ser(939) demonstrated phospho-specific binding to 14-3-3. Glutathione S-transferase pull-down assays with 14-3-3 fusion proteins revealed that all seven 14-3-3 isoforms (beta, gamma, zeta, epsilon, tau, eta, and sigma) could bind tuberin, and this interaction was abrogated by competition with phosphorylated but not unphosphorylated Ser(939) tuberin peptide. Tuberin also coimmunoprecipitated with 14-3-3, confirming the interaction between endogenous 14-3-3 and tuberin. These data establish the presence of functional and overlapping 14-3-3 and Akt recognition site(s) in tuberin.