Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial

Zoulim, Fabien; Fournier, Claire; Habersetzer, François; Sprinzl, Martin; Pol, Stanislas; Coffin, Carla S.; Leroy, Vincent; Ma, Mang; Wedemeyer, Heiner; Lohse, Ansgar W.; Thimme, Robert; Lugardon, Karine; Martin, Perrine; Bastien, Bérangère; Sansas, Benoît; Adda, Nathalie; Halluard, Céline; Bendjama, Kaidre; Brandely, M.; Inchauspé, Geneviève

doi:10.1080/21645515.2019.1651141

Cited by 62 publications

(46 citation statements)

References 43 publications

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“…A non-replicative adenoviral vector harboring HBsAg, HBcAg, and Polymerase (TG1050) was shown to induce strong HBV multi-specific and prolonged T-cell responses in the mouse model (145). A Phase Ib study was performed in CHB patients and demonstrated the safety and immunogenicity of TG1050, supporting future testing in combination with antivirals (146).…”

Section: Dna Vaccinesmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Section: Dna Vaccinesmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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“…The three doses used were 10 9 , 10 10 , 10 11 virus particles of TG1050. All doses were well tolerated in both cohorts and the vaccine was capable of inducing IFN-γ producing T cells that targeted one to three encoded antigens, more so with the 10 10 virus particle dose [ 110 ].…”

Section: Immunotherapymentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

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The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

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“…Among the vectored vaccines, TG1050 has completed Phase Ib trial. 95 TG1050 is an adenovirus serotype 5 vectored vaccine encoding truncated HBV core, a modified HBV DNA polymerase and two HBV envelope domains. IFN-γ producing HBVspecific T cells were produced, but only minor decreases in Figure 13.…”

Section: Discussionmentioning

confidence: 99%

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

Ma¹,

Motyka

Gutfreund

et al. 2019

Human Vaccines & Immunotherapeutics

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In chronic Hepatitis B Virus (HBV) infections HBV-specific T cells are functionally impaired. Immunotherapy may restore HBV-specific T cell responses essential for sustained disease remission offtreatment and induction of a functional cure. Chimigen® Molecules are fusion proteins of antigen(s) with the Fc fragment of a xenotypic antibody designed to target specific receptors on dendritic cells (DCs). Here we describe the production and pre-clinical evaluation of Chimigen® HBV (C-HBV), containing HBV PreS1 and PreS2 peptide fragments, HBV core and murine Fc, produced in insect cells. C-HBV binding to immature DCs and internalization by endocytosis was FcγRII (CD32) and mannose receptor (CD206) dependent and led to increased MHC I and MHC II surface expression. Upon exposure of human T cells isolated from HBV un-infected healthy and chronically HBV-infected donors to C-HBV-pulsed mature DCs ex vivo, C-HBV induced vigorous T cell proliferation and enhanced expression of IFN-γ, TNF-α, perforin and granzyme B in both CD4 + and CD8 + T cell subsets. Re-stimulation of C-HBV-activated T cells from chronically infected donors with HBV PreS1/PreS2 and core overlapping peptides induced IFN-γ production in both CD4 + and CD8 + populations. C-HBV-activation of peripheral blood mononuclear cells (PBMCs) from chronically HBV-infected patients stimulated granzyme B production by CD4 + CD25 − T responder (Tresp) cells, accompanied by an increase in Annexin V staining on CD4 + CD25 + T regulatory (Treg) cell phenotype, consistent with apoptosis. The observed HBV-specific cellular responses induced by C-HBV ex vivo suggest that C-HBV is a promising immunotherapeutic candidate for the treatment of chronic HBV infections.

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Safety and immunogenicity of the therapeutic vaccine TG1050 in chronic hepatitis B patients: a phase 1b placebo-controlled trial

Cited by 62 publications

References 43 publications

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

New Approaches to the Treatment of Chronic Hepatitis B

A dendritic cell receptor-targeted chimeric immunotherapeutic protein (C-HBV) for the treatment of chronic hepatitis B

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