Phase Ib/IIa randomized study of heterologous ChAdOx1HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with CHB

초록

Background & aims: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T-cell dysfunction during CHB. Methods: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. Fifty-five patients with virally suppressed CHB and HBsAg <4,000 IU/ml were enrolled. Group 1 received MVA-HBV intramuscularly on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0 and MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. Results: VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in Group 2: 3 of 18 patients with starting HBsAg <50 IU/ml had durable log(10) declines of >0.7 log(10) at 2 months after the last dose. Group 3 (n = 18) had mean reductions in HBsAg of 0.76 log(10) and 0.80 log(10) (p <0.001) at 2 and 7 months after the last dose. Two patients developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T-cell responses were generated and there was a correlation between IFN-gamma ELISpot response and HBsAg decline in Group 2. Conclusions: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic that warrants further development alone or in combination therapies.

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