编者按：在第54届欧洲肝脏研究学会年会（EASL2019）设立的“研究智库”（Research Think Tank）肝癌专场，西班牙纳瓦拉大学医学院Bruno Sangro教授受邀针对当前及未来的肝癌免疫治疗进行了深入剖析和讲解。演讲结束后，Sangro教授接受了《国际肝病》的采访，就当前免疫治疗在肝癌领域应用的热点问题发表了独到见解。

 

《国际肝病》：当前免疫治疗在肝癌治疗中的地位如何？

 

Sangro教授：免疫治疗是当前肝癌治疗中的生力军。经过在其他肿瘤中的应用，免疫治疗在肝癌中的前景同样令人期待，个人认为在未来免疫治疗将发挥其重要的作用。

 

 Immunotherapy is becoming a fourth arm in the therapies being used in cases of HCC. After being implemented in other tumors, it became clear that the landscape seen in liver tumors is similar to, or least sharing common targets, as that of other tumors. It is logical to apply the same tools that have been successfully applied to other tumors. I consider this is going to be very important in the future.

 

《国际肝病》：目前系统治疗的用药选择上，您是如何为进展期肝癌患者选择合适用药的？

 

Sangro教授：对于进展期肝癌患者，谈最佳的用药选择还为时尚早，目前的临床研究还比较少。但是就目前的研究结果看来，PD-1和CTLA-4的免疫节点抑制剂仍可作为这些患者系统治疗的首选，也是目前可获得性的治疗药物。然而，在其他肿瘤患者中，也有相当比例的患者出现免疫治疗无应答的状况。这提示我们，免疫图谱在肿瘤患者中存在个体差异性。针对上述免疫治疗无应答的患者，我们需要在未来的研究中深挖在免疫图谱背后隐藏的奥秘，继而找到能够进一步提高免疫治疗疗效的有效方法。

 

It is still too early to say which is the best option for these patients, as there are only a few clinical trials that have been reported. But considering the results we have obtained, the first option would obviously be to use the checkpoint inhibitors, such as the PD-1 and CTLA-4 antibodies, for example, with the currently available therapies. As in other tumors, however, there will be a significant proportion of patients who will not respond. It has been shown that many of these patients have different immune profiles in their tumors. I think it is still early, but it is obvious for the future that there needs to be profile measurements of the immune landscapes of these individuals and then tailoring the treatment according to immune response or lack of response to improve the effect of those therapies.

 

《国际肝病》：免疫治疗与小分子靶向药物的联合，对于进展期肝癌患者而言有何临床意义？

 

Sangro教授：免疫治疗与小分子靶向药物的联合，一方面是靶向治疗药物的直接抗肿瘤的疗效，它们能够减轻肿瘤负荷，同时为免疫治疗提供一个更好发挥其作用的一个前提条件。另一个方面，随着靶向治疗药物的不断升级，目前获批的新一代药物同时也具有在免疫作用通路方面的作用靶点，当这些药物再与免疫治疗药物相结合，我们能够达到抗肿瘤的协同作用。

 

Combination therapy has two points of view. One is the direct anti-tumor effect that the targeted drugs may have. They reduce the tumor load, which would contribute to making things easier for the immunotherapy. On the other hand, some of the approved drugs are targeting tyrosine kinases, and it has been shown that these targets may also have some immune modulatory effects. So by combining immunomodulatory drugs, such as immunotherapy, with already approved drugs, such as sorafenib or other tyrosine kinase inhibitors, we can achieve a synergistic effect between the targeted therapies and the classical immunotherapy.

 

《国际肝病》：当前免疫治疗的应用需要克服的主要困难是什么？

 

Sangro教授：首先，我们需要基于患者的治疗效果及其免疫应答类型，对患者进行合理的分类，根据分类我们才能够对患者进行最适合的治疗。当前，我们还缺乏对患者这方面的认识，所以只能够机械地采用“one-size-fits-all”的原则，我们也很难对患者的治疗应答进行预测，这方面必定是我们有待提高的。希望随着越来越多的分子学标志物的发现，我们将能够确定哪些患者存在免疫反应，从而实现患者的个体化治疗。

 

 The first obstacle is to correctly classify patients in terms of their immune response or lack of immune response, and the type of immune response. According to that, we can apply the most appropriate therapy for that patient. At this moment, we cannot effectively determine the immune profile of our patients, so physicians are applying a one-size-fits-all approach to therapy, using nivolumab or pembrolizumab, but it is difficult to predict which ones will be responders. I hope with the development of new biomarkers we will be able to identify the presence or absence of immune responses that will determine the type of treatment that should be applied to each patient.

 

《国际肝病》：请您描绘一下，未来的肿瘤免疫治疗将是怎样的？

 

Sangro教授：未来的肿瘤免疫治疗，将针对个体的免疫应答进行“精准”的治疗。这有赖于我们对各种肿瘤更加细化的分子标签，但由于不同肿瘤可能具有共同的分子标志物，所以最理想的是我们能够找到一个“通用”的肿瘤分子标记模型。就我们所知，淋巴细胞的抗肿瘤活性是相同的，不论是作用于肝癌还是黑色素瘤，因此不同肿瘤通用的免疫分子学标志物模型，理论上可能存在。

 

I am not sure about specific for each organ, but certainly specific for an immune response. It would be great to have specific markers for each tumor, but as the immune responses have been shown to be quite similar in some parameters between organs, the best option would be to have a general biomarker for tumor responses. Lymphocytes are the same in terms of their anti-tumor activities, whether they are acting on a liver tumor or a melanoma. The type of immune biomarkers hopefully would be the same.