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1.
J Immunol ; 209(1): 99-117, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35667841

RESUMO

Persistence of an immunosuppressive state plays a role in septic patient morbidity and late mortality. Both innate and adaptive pathways are impaired, pointing toward the need for immune interventions targeting both arms of the immune system. We developed a virotherapy using the nonpropagative modified vaccinia virus Ankara (MVA), which harbors the intrinsic capacity to stimulate innate immunity, to deliver IL-7, a potent activator of adaptive immunity. The rMVA-human IL-7 (hIL-7)-Fc encoding the hIL-7 fused to the human IgG2-Fc was engineered and shown to express a dimeric, glycosylated, and biologically active cytokine. Following a single i.v. injection in naive mice, the MVA-hIL-7-Fc increased the number of total and activated B, T, and NK cells but also myeloid subpopulations (Ly6Chigh, Ly6Cint, and Ly6Cneg cells) in both lung and spleen. It triggered differentiation of T cells in central memory, effector memory, and acute effector phenotypes and enhanced polyfunctionality of T cells, notably the number of IFN-γ-producing cells. The MVA vector contributed significantly to immune cell activation, particularly of NK cells. The MVA-hIL-7-Fc conferred a significant survival advantage in the cecal ligation and puncture (CLP) and Candida albicans sepsis models. It significantly increased cell numbers and activation in both spleen and lung of CLP mice. Comparatively, in naive and CLP mice, the rhIL-7-Fc soluble counterpart overall induced less vigorous, shorter lasting, and narrower immune activities than did the MVA-hIL-7-Fc and favored TNF-α-producing cells. The MVA-hIL-7-Fc represents a novel class of immunotherapeutic with clinical potential for treatment of septic patients.


Assuntos
Interleucina-7 , Sepse , Imunidade Adaptativa , Animais , Imunidade Inata , Fatores Imunológicos , Imunoterapia , Camundongos , Sepse/terapia , Linfócitos T , Vaccinia virus
2.
Gut ; 64(12): 1961-71, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25429051

RESUMO

OBJECTIVE: To assess a new adenovirus-based immunotherapy as a novel treatment approach to chronic hepatitis B (CHB). METHODS: TG1050 is a non-replicative adenovirus serotype 5 encoding a unique large fusion protein composed of a truncated HBV Core, a modified HBV Polymerase and two HBV Envelope domains. We used a recently described HBV-persistent mouse model based on a recombinant adenovirus-associated virus encoding an over length genome of HBV that induces the chronic production of HBsAg, HBeAg and infectious HBV particles to assess the ability of TG1050 to induce functional T cells in face of a chronic status. RESULTS: In in vitro studies, TG1050 was shown to express the expected large polyprotein together with a dominant, smaller by-product. Following a single administration in mice, TG1050 induced robust, multispecific and long-lasting HBV-specific T cells detectable up to 1 year post-injection. These cells target all three encoded immunogens and display bifunctionality (i.e., capacity to produce both interferon γ and tumour necrosis factor α as well as cytolytic functions). In addition, control of circulating levels of HBV DNA and HBsAg was observed while alanine aminotransferase levels remain in the normal range. CONCLUSIONS: Injection of TG1050 induced both splenic and intrahepatic functional T cells producing cytokines and displaying cytolytic activity in HBV-naïve and HBV-persistent mouse models together with significant reduction of circulating viral parameters. These results warrant clinical evaluation of TG1050 in the treatment of CHB.


Assuntos
Adenoviridae/metabolismo , Linfócitos T CD8-Positivos/metabolismo , DNA Viral/sangue , Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , Imunoterapia/métodos , Proteínas Virais de Fusão/imunologia , Adenoviridae/classificação , Alanina Transaminase/sangue , Animais , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/imunologia , Modelos Animais de Doenças , Produtos do Gene env/genética , Produtos do Gene env/imunologia , Vetores Genéticos , Antígeno HLA-A2/genética , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/sangue , Interferon gama/sangue , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Proteínas Virais de Fusão/genética , Carga Viral
3.
Hum Vaccin Immunother ; 18(6): 2133914, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36315906

RESUMO

Persistence of an immunosuppression, affecting both the innate and adaptive arms of the immune system, plays a role in sepsis patients' morbidity and late mortality pointing to the need for broad and effective immune interventions. MVA-hIL-7-Fc is a non-replicative recombinant Modified Vaccinia virus Ankara encoding the human interleukin-7 fused to human IgG2 Fc fragment. We have shown in murine sepsis models the capacity of this new virotherapy to stimulate both arms of the immune system and increase survival. Herein, an exploratory study in nonhuman primates was performed following a single intravenous injection of the MVA-hIL-7-Fc used at the clinical dose to assess its safety and biological activities. Four cynomolgus macaques were followed for 3 weeks post-injection (p.i), without observed acute adverse reactions. Circulating hIL-7-Fc was detected during the first 3-5 days p.i with a detection peaking at 12 h p.i. IL-7 receptor engagement and downstream signal transduction were detected in T cells demonstrating functionality of the expressed IL-7. Expansion of blood lymphocytes, mainly CD4 and CD8 naïve and central memory T cells, was observed on day 7 p.i. together with a transient increase of Ki67 expression on T lymphocytes. In addition, we observed an increase in circulating B and NK cells as well as monocytes were albeit with different kinetics and levels. This study indicates that a vectorized IL-7-Fc, injected by intravenous route at a relevant clinical dose in a large animal model, is active without adverse reactions supporting the clinical development of this novel virotherapy for treatment of sepsis patients.


Assuntos
Interleucina-7 , Vaccinia virus , Humanos , Camundongos , Animais , Interleucina-7/genética , Imunoterapia , Contagem de Linfócitos , Macaca fascicularis
4.
Hum Vaccin Immunother ; 14(6): 1417-1422, 2018 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-29388874

RESUMO

Pre-clinical models mimicking persistent hepatitis B virus (HBV) expression are seldom, do not capture all features of a human chronic infection and due to their complexity, are subject to variability. We report a meta-analysis of seven experiments performed with TG1050, an HBV-targeted immunotherapeutic, 1 in an HBV-persistent mouse model based on the transduction of mice by an adeno-associated virus coding for an infectious HBV genome (AAV-HBV). To mimic the clinical diversity seen in HBV chronically infected patients, AAV-HBV transduced mice displaying variable HBsAg levels were treated with TG1050. Overall mean percentages of responder mice, displaying decrease in important clinical parameters i.e. HBV-DNA (viremia) and HBsAg levels, were 52% and 51% in TG1050 treated mice, compared with 8% and 22%, respectively, in untreated mice. No significant impact of HBsAg level at baseline on response to TG1050 treatment was found. TG1050-treated mice displayed a significant shorter Time to Response (decline in viral parameters) with an Hazard Ratio (HR) of 8.3 for viremia and 2.6 for serum HBsAg. The mean predicted decrease for TG1050-treated mice was 0.5 log for viremia and 0.8 log for HBsAg, at the end of mice follow-up, compared to no decrease for viremia and 0.3 log HBsAg decrease for untreated mice. For mice receiving TG1050, a higher decline of circulating viremia and serum HBsAg level over time was detected by interaction term meta-analysis with a significant treatment effect (p = 0.002 and p<0.001 respectively). This meta-analysis confirms the therapeutic value of TG1050, capable of exerting potent antiviral effects in an HBV-persistent model mimicking clinical situations.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/terapia , Fatores Imunológicos/uso terapêutico , Animais , DNA Viral/sangue , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Antígenos de Superfície da Hepatite B/sangue , Camundongos Endogâmicos C57BL , Resultado do Tratamento , Carga Viral
5.
Vaccine ; 33(36): 4548-53, 2015 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-26209840

RESUMO

Hepatitis B virus (HBV) infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current therapies based on nucleos(t)ide analogs or pegylated-interferon-α lead to control of viral replication in most patients but rarely achieve cure. A potential strategy to control chronic hepatitis B is to restore or induce functional anti-HBV T-cell immune responses using HBV-specific immunotherapeutics. However, viral diversity is a challenge to the development of this class of products as HBV genotypes display a sequence diversity of up to 8%. We have developed a novel HBV-targeted immunotherapeutic, TG1050, based on a non-replicative Adenovirus vector encoding a unique and large fusion protein composed of multiple antigenic regions derived from a HBV genotype D sequence. Using peripheral blood mononuclear cells from 23 patients chronically infected by five distinct genotypes (gt A, B, C, D and E) and various sets of peptides encompassing conserved versus divergent regions of HBV core we have measured ability of TG1050 genotype D core-derived peptides to be recognized by T-cells from patients infected by various genotypes. Overall, PBMCs from 78% of genotype B or C- and 100% genotype A or E-infected patients lead to detection of HBV core-specific T-cells recognizing genotype D antigenic domains located both in conserved and variable regions. This proof-of-concept study supports the clinical development of TG1050 in large patient populations independently of infecting genotypes.


Assuntos
Epitopos/imunologia , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Vacinas contra Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/terapia , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia , Adenoviridae/genética , Reações Cruzadas , Portadores de Fármacos , Epitopos/genética , Genótipo , Antígenos do Núcleo do Vírus da Hepatite B/genética , Vacinas contra Hepatite B/genética , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Humanos , Proteínas Recombinantes de Fusão/genética , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
6.
Vaccine ; 32(26): 3256-63, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24726690

RESUMO

Development of active targeted immunotherapeutics is a rapid developing field in the arena of chronic infectious diseases. The question of repeated, closely spaced administration of immunotherapeutics to achieve a rapid impact on the replicating agent is an important one. We analyzed here, using a prototype adenovirus-based immunotherapeutic encoding Core and Polymerase from the hepatitis B virus (Ad-HBV), the influence of closely spaced repeated immunizations on the level and quality of induced HBV-specific and vector-specific immune responses in various mouse models. Ad-HBV, whether injected once or multiple times, was able to induce HBV- and adeno-specific T cells both in HBV-free mice and in a HBV tolerant mouse model. Adenovirus-specific T cell responses and titers of neutralizing anti-Ad5 antibodies increased from time of the 3rd injection. Interestingly, single or multiple Ad-HBV injections resulted in detection of Polymerase-specific functional T cells in HBV tolerant mice. Overall no modulation of the levels of HBV-specific cytokine-producing (IFNγ/TNFα) and cytolytic T cells was observed following repeated administrations (3 or 6 weekly injections) when compared with levels detected after a single injection with the exception of two markers: 1. the proportion of HBV-specific IFNγ-producing cells bearing the CD27+/CD43+ phenotype appeared to be sustained in C57BL/6J mice following 6 weekly injections; 2. the percentage of IFNγ/TNFα Core-specific producing cells observed in spleens of HLA-A2 mice as well as of that specific of Polymerase observed in livers of HBV tolerant mice was maintained. In addition, percentage of HBV-specific T cells expressing PD-1 was not increased by multiple injections. Overall these data show that, under experimental conditions used, rapid, closely spaced administrations of an adenovirus-based HBV immunotherapeutics does not inhibit induced T-cell responses including in a HBV-tolerant environment.


Assuntos
Vacinas contra Hepatite B/imunologia , Hepatite B/prevenção & controle , Imunidade Celular , Esquemas de Imunização , Adenoviridae , Animais , Produtos do Gene pol/imunologia , Antígeno HLA-A2 , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Imunoterapia , Interferon gama/imunologia , Fígado/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Baço/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia
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