展望2019年乙肝治疗前景（更新）

齐欢畅

新加坡首次批准用于治疗肝癌的T细胞工程（TCR）免疫疗法
新闻稿PR Newswire
2018年8月19日，下午9点00分

新加坡，2018年8月20日/美通社/ - Lion TCR Pte。总部位于新加坡的Biotech公司获得了新加坡卫生科学管理局（HSA）的批准，用于其产品候选物（LioCyx™）的I / II期多中心临床研究，用于治疗肝移植后复发性肝癌。这是新加坡和该地区的第一项此类试验，该试验使用精确T细胞受体（TCR）免疫细胞疗法来靶向乙型肝炎病毒（HBV）相关的肝癌，该肝癌在亚洲形成至少80％的肝癌。每年世界上80万新肝癌病例中有80％在亚太地区被诊断出来，包括中国，越南，泰国，印度尼西亚，韩国和新加坡。肝癌是世界上第三大致命癌症，治疗选择非常有限，治疗结果也很差。目前对于肝移植后肝癌复发患者没有有效的治疗方法。

LioCyx™由Lion TCR的科学创始人，世界着名的HBV肝癌临床科学家Antonio Bertoletti教授开发。在新加坡和中国，一些由Investigator赞助的LioCyx™试验显示出良好的安全性和令人鼓舞的疗效迹象。 “我们非常高兴LioCyx™的I / II期临床试验得到批准，LioCyx™是新加坡第一个用于治疗肝癌的TCR-T细胞疗法。这是对患者对创新疗法的认可的极大鼓励。新加坡HSA一直非常高效，透明和专业地审查我们的创新免疫疗法临床试验申请“，Lion TCR创始人兼首席执行官Victor Li Lietao博士说。

I / II期临床试验的患者招募将从新加坡国立大学医院（NUH）开始。 Lion TCR正在将新加坡和中国的医疗中心纳入审判范围。

关于Lion TCR

Lion TCR是一家总部位于新加坡的临床阶段生物技术公司，专注于开发针对病毒相关癌症和慢性乙型肝炎的工程化T细胞免疫疗法，并在中国和新加坡进行制造和临床试验。它是世界上第一家开发针对肝癌的HBV特异性TCR T细胞疗法的公司。

Lion TCR的工程T细胞技术由新加坡科学，技术和研究机构（A * STAR）（由Antonio Bertoletti教授的实验室开发的TCR-T细胞疗法）和慕尼黑技术大学（CAR-T细胞）独家授权由Urlike Protzer教授的实验室开发的治疗方法。

Lion TCR最近筹集了2000万美元的新投资，以推进LioCyx™在中国和新加坡各大医院的临床试验，以及扩大其产品管道以对抗病毒相关实体瘤和清除慢性乙型肝炎。

有关Lion TCR的更多信息，请访问http://www.liontcr.com/或联系[email protected]

齐欢畅

TCR--T疗法确实很牛，好多公司在研究。可惜，价格太高，上市不知道要多久。还需要继续研究。

buhaobuhuai

实话说，感觉未来二十年内，甚至更长时间都很难出现治愈药物，毕竟病毒dna与常规细胞dna缠绕在一起。庆幸的是出现越来越多控制病毒的药物，这为最终的胜利提供了时间。个人觉得器官移植应该是个不错的选择。可惜克隆技术不允许使用。

StephenW

我再次发表温玉梅教授的这篇文章:
https://www.nature.com/articles/s41426-018-0092-3
"慢性乙型肝炎功能性治疗的“三明治”策略"


Replicor / Arrowhead药物能够显着降低HbsAg, 您可以考虑干扰素的作用:
1.降解cccDNA，因此进一步减少HbsAg的产生?
2.作为细胞因子，刺激免疫系统?

这个“三明治”策略能否取代干扰素的需要??


A “sandwich” strategy for functional cure of chronic hepatitis B

    Xuan-Yi Wang & Yu-Mei Wen

Emerging Microbes & Infectionsvolume 7, Article number: 91 (2018) | Download Citation

Dear Editor,

Hepatitis B virus (HBV) belongs to the ortho-hepadnaviridae, with a partial circular DNA genome, encoding the surface protein (HBsAg), core protein (HBcAg), X protein (HBxAg), and HBV polymerase. HBV replicates via an RNA intermediates and forms a covalently closed circular DNA (cccDNA) in cellular nuclei, which can be replenished to persistently express viral proteins and replication. Uniquely, the small spherical HBsAg particles transcribed by the viral genome reside in the sera of HBV-infected individuals can reach a number of as high as 1012–14/ml. Furthermore, HBsAg is the major protein that antagonizes various host immune mechanisms, which is one of the major mechanisms for HBV persistence in hosts.

Despite the remarkable success of hepatitis B prophylactic vaccination program in many countries, there are still more than 240 million people worldwide chronically infected with HBV, and up to one million deaths every year is caused by HBV-related cancer or end stage liver diseases1. Therefore, chronic hepatitis B (CHB) is of global concern. Currently, only anti-HBV nucleosides (nucleotides) drugs and interferon-α (IFN-α) are licensed for treatment of the CHB patients. The anti-HBV drugs only target the reverse transcriptase domain of HBV polymerase, which can effectively inhibit the replication of HBV, and decrease the viral load, but these drugs have no inhibitory effects on HBV cccDNA. Similarly, IFN-α only nonspecifically inhibits viral replication and regulates certain immune response, and has no effects on cccDNA either. Since the current treatment cannot eliminate HBV or cure HBV infection, life-long treatment with antiviral or IFN-α is inevitable, with the risk of developing drug resistance or severe side effects.

As the goal of complete elimination of HBV in CHB patients is difficult to attain, in recent years, a consensus has been reached aiming at “functional cure” for the CHB patients. The definition of functional cure includes durable HBsAg loss (with or without HBsAg sero-conversion), undetectable serum HBV DNA, persistence of cccDNA in a transcriptionally inactive status, and the absence of spontaneous relapse after the cessation of treatment2. Previously, two interrelated arms of the CHB therapies, namely antiviral treatment and immunotherapies, have been explored and some are under clinical trials. To achieve functional cure, these two approaches should be upgraded, by which, antiviral treatment should be effective in both inhibiting HBV replication and decreasing serum HBsAg, while immune therapy should restore adaptive immune responses versus HBV to provide long-term immune control of HBV against spontaneous relapse after cessation of treatment.

Recently, several reports observed that by either “early switch to” or “late add-on” combination of antiviral drugs with peg-IFN showed additive effects to certain extent3. When patients under long-term antiviral drug treatment resulted in low-level of serum HBsAg (<3 log of serum HBsAg), clearance of HBsAg was observed in some patients, when they further received peg-IFN treatment4, 5. These findings seemed to be due to IFN’s effects on cccDNA in HBV-infected cells. Interferon has been shown to trigger non-cytolytic degradation of cccDNA in infected cells, and activation of nuclear deaminases, resulted in cccDNA deamination leading to a significant reduction of cccDNA6. These observations provided clues to employ different immune therapies in patients with low levels of HBsAg, and several clinical trials are undergoing7. In addition, human anti-HBs and anti-pre-S1-monoclonal antibodies have been developed recently and have shown to clear serum HBsAg in different mouse models8,9,10. These studies provide renewed interest of employing neutralizing antibodies as a therapeutic approach against serum HBsAg.

As only few CHB patients under long-term antiviral treatment can reach a significant decrease in serum HBsAg. Of these, only a part of the individuals with further treatment may reach functional cure. While human neutralizing anti-HBs/anti-Pre S1 antibodies may help to decrease the load of serum HBsAg, we herein propose a “sandwich” approach to expedite the decrease of serum HBsAg in the CHB patients, and to induce potent-specific immune responses to prevent spontaneous relapse after the cessation of treatment. This approach consists of the following protocols: (1) use antiviral drugs to inhibit viral replication and decrease serum viral load, throughout the whole therapeutic process as the first layer of sandwich; (2) employ potent neutralizing monoclonal anti-HBs antibodies to decrease serum HBsAg levels, mimicking the decrease of HBsAg after long-term antiviral therapy as the second layer of sandwich; and, (3) when patients were free from serum HBV DNA and HBsAg, with a transient “window stage” similar to normal adults, potent-specific active immunization should be applied to induce effective host immune responses serving as the last layer. A diagram of the most optimistic expected therapeutic efficacy of this strategy is shown in Figure 1.
Fig. 1
Fig. 1

Diagram of expected therapeutic efficacy under proposed “sandwich” strategy
Full size image

The uniqueness of this approach is by two combinations, one is the combination between antiviral drugs and immunotherapy, the other is by combination of passive and active immunization. Neutralizing anti-HBs human antibodies, can neutralize HBV via the Fab fragment, while the Fc fragment can further enhance host immune response via multiple mechanisms, such as ADCC, etc.11, 12. A cocktail of anti-HBs and anti-pre-S1-monoclonal antibodies may jointly block the entry of HBV to infect new hepatocytes, and restore damaged host immune responses exerted by high levels of HBsAg10. So far, though active immunization by therapeutic vaccination in CHB patients showed limited efficacy, restoration of CD4+ and CD8+ cell functions, decrease of Treg cells, and effective HBeAg sero-conversion, as well as one-log decrease of serum HBsAg have been observed in clinical trials of HBsAg-HBIG immune complex therapeutic vaccine13, 14. Furthermore, very low levels of B cells against HBsAg have been observed in the CHB patients15. These cells, probably inactivated by the persistence of HBsAg, may restore their active functions via potent active immunization, and help to prevent spontaneous relapse after cessation of treatment.

Though this “sandwich” approach seems applicable, the short “window stage” of transient clearance of serum HBsAg is critical for successful treatment of CHB patients. “Add on” or different sequential protocols need to be explored to make use of this stage, and potent active immunization should be explored. To avoid possible side effects, liver functions, humoral, and cellular immune responses should be closely monitored during this protocol of treatment. In addition, different active immunization regimens, such as, DNA vaccination, vector-mediated vaccines, usage of different adjuvants, etc., are all possible approaches that should be studied to maximize the desired anti-HBV immune responses. As all approaches for CHB functional cure can only be verified by clinical trials, we hope the approach presented in this article can be considered for international collaboration, and granted approval for pilot clinical trials in the near future, to benefit patients suffering from the consequences of CHB.

乙型肝炎病毒（HBV）属于邻嗜肝DNA病毒科，具有部分环状DNA基因组，编码表面蛋白（HBsAg），核心蛋白（HBcAg），X蛋白（HBxAg）和HBV聚合酶。 HBV通过RNA中间体复制并在细胞核中形成共价闭合环状DNA（cccDNA），可以补充其持续表达病毒蛋白和复制。独特地，由病毒基因组转录的小球形HBsAg颗粒存在于HBV感染个体的血清中，可达到高达1012-14 / ml的数量。此外，HBsAg是拮抗各种宿主免疫机制的主要蛋白质，这是宿主中HBV持续存在的主要机制之一。

尽管许多国家的乙型肝炎预防性疫苗接种计划取得了显着成功，但全球仍有超过2.4亿人慢性感染HBV，每年有多达100万人死于HBV相关癌症或终末期肝病1。因此，慢性乙型肝炎（CHB）是全球关注的问题。目前，只有抗HBV核苷（核苷酸）药物和干扰素-α（IFN-α）被许可用于治疗CHB患者。抗HBV药物仅针对HBV聚合酶的逆转录酶结构域，可有效抑制HBV的复制，降低病毒载量，但这些药物对HBV cccDNA无抑制作用。类似地，IFN-α仅非特异性地抑制病毒复制并调节某些免疫应答，并且对cccDNA也没有影响。由于目前的治疗方法不能消除HBV或治愈HBV感染，因此不可避免地要用抗病毒药或IFN-α进行终身治疗，存在产生耐药性或严重副作用的风险。

由于难以实现在CHB患者中完全消除HBV的目标，近年来，已经达成了针对CHB患者的“功能性治愈”的共识。功能性治愈的定义包括持久的HBsAg消失（有或没有HBsAg血清转换），检测不到的血清HBV DNA，cccDNA在转录无活性状态下的持久性，以及停止治疗后没有自发复发2。以前，已经探索了CHB疗法的两个相互关联的臂，即抗病毒治疗和免疫疗法，并且一些正在进行临床试验。为了实现功能性治愈，应该升级这两种方法，通过这种方法，抗病毒治疗应该有效抑制HBV复制和降低血清HBsAg，而免疫治疗应该恢复对HBV的适应性免疫应答，以提供HBV的长期免疫控制。停止治疗后自发复发。

最近，一些报道观察到，通过“早期转换为”或“晚期添加”，抗病毒药物与peg-IFN的组合在一定程度上显示出累加效应3。当长期抗病毒药物治疗的患者血清HBsAg水平低（血清HBsAg <3 log）时，一些患者在进一步接受peg-IFN治疗时观察到HBsAg的清除4,5。是由于IFN对HBV感染细胞中cccDNA的影响。已经显示干扰素引发感染细胞中cccDNA的非细胞溶解降解，并且核脱氨酶的活化导致cccDNA脱氨基导致cccDNA6的显着减少。这些观察结果提供了在HBsAg水平低的患者中采用不同免疫疗法的线索，并且正在进行一些临床试验7。此外，最近已经开发出人抗-HBs和抗-pre-S1-单克隆抗体，并且已经显示在不同的小鼠模型中清除血清HBsAg 8,9,10。这些研究提供了使用中和抗体作为抗血清HBsAg治疗方法的新兴趣。
由于只有少数长期抗病毒治疗的CHB患者血清HBsAg明显降低。其中，只有一部分进一步治疗的患者可以达到功能性治愈。虽然人中和抗HBs /抗Pre S1抗体可能有助于降低血清HBsAg的负荷，但我们在此提出了一种“三明治”方法，以加速CHB患者血清HBsAg的降低，并诱导强效特异性免疫应答防止停止治疗后自发复发。该方法包括以下方案：（1）使用抗病毒药物来抑制病毒复制并降低血清病毒载量，在整个治疗过程中作为第一层夹心; （2）采用强效中和单克隆抗HBs抗体降低血清HBsAg水平，模拟长期抗病毒治疗后HBsAg降低为第二层三明治; （3）当患者不含血清HBV DNA和HBsAg时，具有与正常成人相似的短暂“窗口期”，应采用强效特异性主动免疫来诱导有效的宿主免疫应答作为最后一层。图1显示了该策略最乐观的预期治疗效果图。
图。1
图。1

拟议的“三明治”策略下的预期治疗效果图
全尺寸图片

这种方法的独特之处在于两种组合，一种是抗病毒药物与免疫疗法的结合，另一种是被动和主动免疫的结合。中和抗HBs人抗体可通过Fab片段中和HBV，而Fc片段可通过多种机制进一步增强宿主免疫应答，如ADCC等.11,12抗HBs和抗前体的混合物S1-单克隆抗体可以联合阻断HBV的进入以感染新的肝细胞，并恢复由高水平HBsAg10施加的受损宿主免疫应答。到目前为止，尽管CHB患者通过治疗性疫苗接种进行的主动免疫接种效果有限，但CD4 +和CD8 +细胞功能恢复，Treg细胞减少，HBeAg血清转换有效，血清HBsAg降低1个百分点。 HBsAg-HBIG免疫复合物治疗性疫苗的临床试验13,14。此外，在CHB患者中观察到非常低水平的针对HBsAg的B细胞15。这些细胞可能因HBsAg持续存在而失活，可通过有效的主动免疫恢复其活性功能，并有助于防止停止治疗后自发复发。
尽管这种“三明治”方法似乎适用，但血清HBsAg短暂清除的短暂“窗口阶段”对于成功治疗CHB患者至关重要。需要探索“添加”或不同的顺序方案以利用这一阶段，并应探索有效的主动免疫。为避免可能的副作用，应在本治疗方案中密切监测肝功能，体液和细胞免疫应答。此外，不同的主动免疫方案，例如DNA疫苗接种，载体介导的疫苗，不同佐剂的使用等，都是应该研究以使所需的抗HBV免疫应答最大化的可能方法。由于所有CHB功能治愈的方法都只能通过临床试验来验证，我们希望本文介绍的方法可以考虑用于国际合作，并在不久的将来批准试验性临床试验，以使患有后果的患者受益。 CHB。

齐欢畅

回复 StephenW 的帖子

免疫策略已经是公认的研究方向，乙肝是自限性病毒，人体本来就可以清除这类病毒，所以我觉得未来我们的关注焦点还是在免疫药物。
当然抗病毒效果越来越好了，现在的药物，也是值得庆贺的事。

newchinabok

齐欢畅 发表于 2018-9-12 21:25
回复 StephenW 的帖子

免疫策略已经是公认的研究方向，乙肝是自限性病毒，人体本来就可以清除这类病毒，所 ...

免疫治疗就几大类，5个指头数得过来

newchinabok

一种“三明治”方法，以加速CHB患者血清HBsAg的降低，并诱导强效特异性免疫应答防止停止治疗后自发复发。该方法包括以下方案：（1）使用抗病毒药物来抑制病毒复制并降低血清病毒载量，在整个治疗过程中作为第一层夹心; （2）采用强效中和单克隆抗HBs抗体降低血清HBsAg水平，模拟长期抗病毒治疗后HBsAg降低为第二层三明治; （3）当患者不含血清HBV DNA和HBsAg时，具有与正常成人相似的短暂“窗口期”，应采用强效特异性主动免疫来诱导有效的宿主免疫应答作为最后一层

newchinabok

简单说，先降dna（核苷药），再降hbsag（中和抗体），再强免疫（dna疫苗，载体疫苗）。=治愈

齐欢畅

不错

newchinabok

齐欢畅 发表于 2018-9-12 22:33
不错

简单，粗暴的方法好不好？哈哈，一看就懂。