西班牙纳瓦拉大学医学院Pablo Sarobe教授访谈

 

编者按：当下，肿瘤治疗已迈入免疫治疗时代。在第54届欧洲肝脏研究学会年会（EASL2019）基础科学研讨会上，西班牙纳瓦拉大学医学院Pablo Sarobe教授受邀做的一场关于“肝脏免疫和免疫治疗”的专题报告吸引着众多与会者的目光。那么，免疫治疗时代下，肿瘤患者可能实现治愈吗？请与我们一起聆听《国际肝病》在大会现场对Sarobe教授进行的独家专访……

 

《国际肝病》：针对进展期肝癌的免疫治疗近年来有哪些新药物及应用进展？

 

Sarobe教授: 近5年来，免疫检查点抑制剂已在进展期肝癌患者中开展了研究，结果表明该药能诱导15%~20%患者的客观缓解，从而延长生存。关于免疫检查点抑制剂是否对大多数肝癌患者有治疗获益的临床研究，我们也期待公布最终的结果。通过这些研究，我们将揭晓在未经选择的肝癌患者中应用免疫检查点抑制剂，是否与那些有治疗应答的人群一样有显著地生存获益。

 

当免疫微环境存在耐受，机体的免疫应答受到抑制，肿瘤细胞将迅速生长。免疫检查点抑制剂就是试图将免疫微环境的状态调回到正常的免疫应答状态，从而抑制肿瘤细胞的生长。

 

在美国，Nivolumab主要适用于晚期肝癌患者，包括存在肝外转移、巨大肝脏肿瘤、肝内血管侵犯或肝门静脉血栓的肝癌患者，在索拉非尼标准的一线治疗后，一旦出现疾病进展或者由于治疗的不良反应不耐受，则可以选择Nivolumab进行治疗。

 

Over the last five years, what we call the immune checkpoint inhibitors (drugs that release the brakes that the tumor poses to the immune system so cytotoxic T lymphocytes are able to attack the tumor cells) have been studied in patients with advanced HCC, and have been shown to be able to induce objective remissions in around 15-20% of patients. These remissions are followed by prolonged survival, and there are now trials waiting to report whether these agents will be of benefit to a majority of patients. If we treat unselected HCC patients with these drugs, will they significantly prolong survival in that general population and not just in known responders?

 

Cells within the tumor, as well as surrounding stromal cells (macrophages, fibroblasts, and other cells within the tumor microenvironment), release factors and signals causing a state of exhaustion of the lymphocytes. These exhausted lymphocytes are then not able to kill tumor cells appropriately. These are the brakes that the tumor applies to the immune response. The checkpoint inhibitors release those brakes so the immune system is free to act against the tumor.

 

more rapidly and with more ease than if the environment were non-immunosuppressive. That is what these drugs do. They try to turn a suppressive environment into a permissive environment for immune cells.

 

These will be patients who have an advanced stage tumor - with extrahepatic metastases or a large tumor burden inside the liver, and particularly those with vascular invasion into the hepatic or portal veins. These three categories are the advanced stage patients, and once they have progressed on sorafenib, which is standard of care, or if they are intolerant of sorafenib due to side effects, then they qualify for nivolumab therapy (in the United States).

 

=《国际肝病》：您认为免疫治疗时代下，肿瘤患者可能实现治愈吗？

 

Sarobe教授：个人认为失望与希望并存。积极的一面是，我们经历过一些治疗疗效非常好的患者，长期的临床随访显示，患者的肿瘤清除可以长达4~5年。从这个角度来说，这些患者已经实现了治愈。然而，如果把这当做定论来说，那就是夸大了。目前来说，这只能当做偶然事件。我们希望通过药物的联合以及不同的治疗策略来提高免疫治疗的有效性。

 

未来的研究主要集中在以下两方面：首先，我们必须发开出一些工具帮助我们筛选出治疗应答好的患者，对他们而言治愈的可能非常高。目前，免疫治疗药物还很昂贵，现有的医疗资源也还不允许我们将这些药物应用于那些不太可能有治疗获益的人群。因此，治疗前患者的筛选非常有必要。其次，令人兴奋的是，当我们将免疫检查点抑制剂与其他免疫疗法或其他靶向药物相结合时，患者的预后有了显著提高。未来，联合治疗在提高肝癌患者疗效方面存在很大的空间。

 

 Yes and no. Yes, because we all have the experience of patients who have had their tumors cleared for very long periods of time (4-5 years). That is all the follow-up we have available in these patients, as these are still new drugs. If you remain tumor-free without therapy for 4-5 years, it is very likely we can say that patient has been cured. But, that may be an overstatement if the take-home message is that this is a common event after immunotherapy. It is not. It is a rare event. Nevertheless, it is hoped that by combining agents and using different strategies, we can enhance this activity of the immunotherapies.

 

There are two things. We have to develop tools that will allow us to identify those patients who will respond best. For those patients, the chances of a cure will be higher. And we are talking about therapies that are very costly. The system does not allow us to treat those patients with a low chance of getting treatment benefit. So we definitely need tools to better select patients for immunotherapies. The second thing I am excited about is that we have started to see that when we combine immunotherapy with other immunotherapies or other targeted agents, the outcomes are much better. By combining therapies, we can increase patient and treatment benefits.