强干扰素诱导病毒载体与低剂量 Nivolumab 加 Ipilimumab 的顺序组

StephenW

强干扰素诱导病毒载体与低剂量 Nivolumab 加 Ipilimumab 的顺序组合可提供慢性乙型肝炎病毒感染的功能性治疗：提出新模式的技术报告
Tibor Bakacs 1 , Rifaat Safadi 2 , László G Puskás 3 , Liliána Z Fehér 3 , Imre Kovesdi 4
隶属关系
隶属关系

    1
    概率系，Alfred Renyi 数学研究所，Eotvos Lorand 研究网络 (ELKH)，匈牙利布达佩斯。
    2
    肝脏科，Hadassah 医疗组织，Hadassah 希伯来大学医学中心，耶路撒冷，ISR。
    3
    药物开发，AVIDIN 有限公司，塞格德，匈奴。
    4
    病毒学，ImiGene, Inc.，美国罗克维尔。

    PMID：35371882 PMCID：PMC8970536 DOI：10.7759/cureus.22750

抽象的

根据国际消除乙型肝炎病毒联盟 (ICE-HBV) 的建议，我们打算模拟 HBV 感染的自发消退，以实现慢性乙型肝炎病毒 (HBV) 感染的功能性治愈。为此，我们提出了先天性和适应性宿主免疫反应的顺序靶向。 HBV 复制和乙型肝炎表面抗原 (HbsAg) 产生的长期抑制将首先通过诱导强烈的先天免疫反应来实现。将实施经临床验证的病毒二重感染疗法 (SIT)，该疗法采用减毒、非溶解、双链 RNA (dsRNA) 传染性法氏囊病病毒 (IBDV)，可提供异常强的干扰素 (IFN) 反应。然后，通过免疫检查点抑制剂 (ICIs) 阻断细胞毒性 T 淋巴细胞相关抗原 4 (CTLA-4) 和程序性细胞死亡蛋白 1 (PD-1) 受体，将恢复耗尽的 HBV 特异性 T 细胞功能。为了将任何毒性风险降至最低，将给予超说明书低剂量的纳武单抗（0.5 mg/kg）加易普利姆玛（0.3 mg/kg），其安全性和有效性已在 131 例未选择的 IV 期癌症中得到证实耐心。我们预测，这种联合疗法将在相对较短的治疗期内提供持续的非治疗病毒学和临床反应。

关键词：人工病毒血症；减毒病毒疫苗载体；慢性乙型肝炎感染；功能性治愈；易普利姆玛；纳武利尤单抗；标签外低剂量检查点抑制剂；病毒二重感染治疗。

版权所有 © 2022，Bakacs 等人。

StephenW

Sequential Combination of a Strong Interferon Inducer Viral Vector With Low Doses of Nivolumab Plus Ipilimumab Could Provide Functional Cure in Chronic Hepatitis B Virus infections: Technical Report Proposing a New Modality
Tibor Bakacs  1 , Rifaat Safadi  2 , László G Puskás  3 , Liliána Z Fehér  3 , Imre Kovesdi  4
Affiliations
Affiliations

    1
    Department of Probability, Alfred Renyi Institute of Mathematics, The Eotvos Lorand Research Network (ELKH), Budapest, HUN.
    2
    The Liver Unit, Hadassah Medical Organization, Hadassah Hebrew University Medical Center, Jerusalem, ISR.
    3
    Drug Development, AVIDIN Ltd., Szeged, HUN.
    4
    Virology, ImiGene, Inc., Rockville, USA.

    PMID: 35371882 PMCID: PMC8970536 DOI: 10.7759/cureus.22750

Abstract

Based on the recommendation of the International Coalition to Eliminate hepatitis B virus (ICE-HBV), we intend to mimic the spontaneous resolution of HBV infection to achieve a functional cure of chronic hepatitis B virus (HBV) infection. To this end, we propose sequential targeting of the innate and adaptive host immune responses. Long-term suppression of HBV replication and hepatitis B surface antigen (HbsAg) production will be achieved first by inducing a strong innate immune response. The clinically validated viral superinfection therapy (SIT) will be administered, which employs an attenuated, non-lytic, double-stranded RNA (dsRNA) infectious bursal disease virus (IBDV) that provides an exceptionally strong interferon (IFN) response. Then, the exhausted HBV-specific T cell function will be restored by blocking the cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptors with immune checkpoint inhibitors (ICIs). In order to minimize any risk of toxicity, off-label low doses of nivolumab (0.5 mg/kg) plus ipilimumab (0.3 mg/kg) will be administered, the safety and efficacy of which has already been demonstrated in 131 unselected stage IV cancer patients. We predict that this combination therapy will provide sustained off-treatment virological and clinical responses during a relatively short treatment period.

Keywords: artificial viremia; attenuated viral vaccine vector; chronic hepatitis b infection; functional cure; ipilimumab; nivolumab; off-label low dose checkpoint inhibitors; viral superinfection therapy.

Copyright © 2022, Bakacs et al.