编者按：近年来，新兴免疫联合疗法在肝癌领域取得了突破性进展，使晚期肝细胞癌（HCC）患者生存期大幅延长。2021年第56届欧洲肝脏研究学会年会（EASL2021）暨国际肝脏会议TM（ILC2021）上，国际肝癌协会（ILCA）主席、西班牙纳瓦拉大学Bruno Sangro教授应邀进行主题演讲，在“Jean-Pierre Benhamou clinical state-of-the-art”专题介绍这一前沿疗法的最新进展。《国际肝病》记者有幸采访到Sangro教授，请他就相关热点问题发表个人观点。
 

 

 

《国际肝病》：请您简要介绍目前可获得或正在研发中的HCC免疫治疗策略？

 

Bruno Sangro教授：已经有免疫疗法成为晚期HCC患者的标准治疗方法，即PD-L1免疫检查点抑制剂阿替利珠单抗与VEGF血管生成抑制剂贝伐珠单抗的组合，其已获得美国FDA、EMA和其他监管机构的上市批准。当然，在III期临床试验中，还有其他组合正在研发中，例如与酪氨酸激酶抑制剂（TKI）的组合，或免疫检查点抑制剂PD-1/PD-L1单抗与CTLA-4单抗的组合。

 

除此之外，还有处于不同研发阶段的其他策略，例如过继性T细胞免疫疗法，即通过输注可特异性识别肿瘤细胞的T细胞来杀伤癌细胞。此外，还有正在研发中的疫苗策略。

 

总体而言，我们已经创建了多个免疫治疗方法，并且正在对这些治疗方法进行研究。

 

: Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Could you please briefly introduce the HCC immunotherapy strategies currently available or under development?

 

Prof. Bruno Sangro: There are already immunotherapy treatments that are the standard-of-care for patients with advanced hepatocellular carcinoma. Those are the combination of the PD-L1 inhibitor, atezolizumab, with the VEGF inhibitor, bevacizumab. This is approved by the FDA, EMA and other regulatory agencies. 

 

There are other combinations that are being developed with research in phase III trials – combinations with tyrosine kinase inhibitors, or combinations of PD-1/PD-L1 inhibitors with CTLA-4 inhibitors. 

 

After that, there are other strategies in different stages of development, like adoptive T-cell therapy, with cells engineered to recognize tumor cells specifically. Also, there are vaccination strategies in development. So we have established therapies, and therapies that are in development.

 

《国际肝病》：目前哪些患者可从HCC免疫疗法中获益？

 

Bruno Sangro教授：目前批准的免疫治疗组合仅在晚期患者中显示出疗效。这意味着，目前只是伴有肝外转移、门静脉或肝静脉侵犯，以及不适合经肝动脉治疗的这部分患者可以从这些组合中受益。

 

: For the currently available HCC immunotherapy, how do you think it should be used?

 

Prof. Bruno Sangro: The currently approved immunotherapy combinations have only shown efficacy in patients in the advanced stage – that means patients with extrahepatic metastases or vascular invasion to the portal vein or hepatic veins or a large bulk of disease that makes patients not candidates for intra-arterial therapies. Those are the patients that may benefit from these combinations.

 

《国际肝病》：您认为HCC免疫检查点抑制剂治疗面临的主要挑战是什么？

 

Bruno Sangro教授：首先，我们忽略了免疫检查点抑制剂疗法与经导管动脉化疗栓塞术（TACE）联合治疗用于早期和中期患者是否有效，以及在肝切除或消融术后的辅助治疗中是否有效。我们需要知道这个问题的答案。其次，只有一部分患者对这些免疫疗法有反应。需要生物标志物来帮助我们选择免疫疗法的最佳候选者。

 

: What do you think are the main unsolved challenges in HCC checkpoint immunotherapy?

 

Prof. Bruno Sangro: First, we ignore if the immune checkpoint inhibitor therapies would work in the earlier stages in combination with TACE, in the intermediate stage, and in the adjuvant setting after resection or ablation. We ignore that, and we need to know that. Second, only a fraction of the patients respond to these immunotherapies. There is a need for biomarkers that will help us select the best candidates for immunotherapy.

 

《国际肝病》：目前对于免疫治疗的疗效预测和精准选择获益人群有哪些观点？

 

Bruno Sangro教授：我们今天没有足够好的生物标志物来做出临床决策。我们知道，肿瘤内炎症反应越强的患者效果越好，这部分患者有更多的机会获得治疗应答并延长生存期。此外，我们知道，在肿瘤中表达PD-L1的患者也有更高的治疗应答可能和更长的存活时间。

 

但是这两个因素还不能应用于临床，因为非炎症性肿瘤患者和无肿瘤内PD-L1表达的患者也可能对免疫治疗反应很好。迄今为止，我们还无法确定哪些患者对治疗反应更好。对所有患者进行治疗并确定早期应答情况是有意义的，可以使患者获得最佳治疗效果。

 

 : What are the current views regarding the prediction of the efficacy of immunotherapy and the precise selection of the beneficiaries?

 

Prof. Bruno Sangro: We don’t have biomarkers that are good enough to make clinical decisions today. We know that patients with more intra-tumoral inflammation do better – they have more chances to respond and achieve a prolonged survival. We know that patients who have expression of PD-L1 in the tumor also have increased chances of responding and surviving longer. 

 

But these two factors are not ready for clinical use, because patients with non-inflammed tumors, and patients without PD-L1 expression may respond very well to immunotherapy as well. As of today, we cannot say that there are specific patients who respond better. It is worth treating all patients and identifying early responses so that patients could get the best treatment benefit.

 

《国际肝病》：您如何评价以免疫检查点抑制剂为基础的联合疗法前移至早中期HCC？

 

Bruno Sangro教授：以免疫检查点抑制剂为基础的联合疗法在早中期HCC的应用确实是一个未满足的临床需求。我们不应该想当然地认为，免疫疗法在晚期HCC起作用，所以它们应该在早期HCC也能发挥作用，尽管我们非常希望这是真的。

 

正在进行的临床试验已经招募了大量患者，我相信在接下来的1～3年内，我们将对以免疫检查点抑制剂为基础的联合疗法用于早期患者是否有意义有充分的了解。但是到目前为止，我们应该避免过早用于早期患者，因为免疫疗法也会产生毒性。在没有证据支持早期适应证的情况下，早期患者仅应在临床试验中接受这类治疗。

 

: What do you think about the advancement of checkpoint inhibitor-based combination therapies to early and mid-stage hepatocellular carcinoma?

 

Prof. Bruno Sangro: This is truly an unmet need. We should not take for granted that because immunotherapies are working in the advanced stage, they should work in earlier stages. But we have to hope this is indeed true. There are ongoing trials that have already recruited lots of patients, and I am sure that in the next 1-3 years we will have a full idea of whether it is worth treating patients in earlier stages. So far, we should refrain from this because immunotherapies can also produce toxicities. In the absence of evidence supporting the use in earlier stages, patients should only be included in clinical trials.

 

《国际肝病》：基于免疫联合靶向方案的突出疗效，中国学者已经在积极探索晚期HCC向可切除和肿瘤获益的转化治疗，并出台相关专家共识指导临床应用。您怎么看转化治疗？

 

Bruno Sangro教授：我认为这是一个非常重要的方案，因为我们看到对治疗反应良好的晚期患者的肿瘤有明显缓解，有时可使不可切除患者获得切除机会。我确实相信有转化治疗的空间，因为这些患者可能会受益于随后的肝切除或消融，甚至TACE或放射栓塞治疗。

 

但在我们向所有人推荐这个策略之前，我们需要用对照组进行临床试验，如此我们才能确定接受这些治疗的患者比不接受治疗的患者获益更多。确实，免疫疗法有时非常有效，患者可以实现长期完全缓解。

 

转化治疗是一个非常有趣的方案，但我们需要临床试验来验证。中国医生是肝切除和消融方面的专家，因此中国是开展这些试验的理想场所。

 

: Based on the outstanding efficacy of the immune-targeted combination therapy, Chinese scholars have been actively exploring the conversion to resection and oncology benefits for advanced hepatocellular carcinoma, and issued relevant expert consensus to guide clinical application. What do you think of conversion therapy?

 

Prof. Bruno Sangro:  I think this is a very relevant scenario, because we are seeing that patients in the advanced stage who respond well to therapy have a substantial tumor remission, and sometimes these make unresectable patients resectable. I do believe there is room for conversion therapy as these patients may benefit from subsequent resection or ablation or even TACE or radioembolization. 

 

What we need is before we recommend this for everyone is to run clinical trials with a control arm so we can make sure that the patients who receive these therapies do better than patients who don’t. Sometimes, immunotherapies are so potent that you can achieve long-term complete remissions. We need clinical trials to answer this question, but this is a very interesting scenario. Chinese doctors are experts in resection and ablation, and therefore China is a perfect place for running these trials.

 

《国际肝病》：在免疫治疗引领的新时代，您怎么评价HCC的治疗目标？

 

Bruno Sangro教授：对包括肝癌患者在内的癌症患者进行任何治疗的目标都是延长生存期。我们知道，在肝癌中，这通常是多学科协作管理的结果。可以及早切除肿瘤的患者可能有治愈的机会。现在有了免疫疗法，我们很有可能会增加治愈的患者数量。可以肯定的是，我们已经增加了可实现长期生存的患者数量，即便患者处于晚期。

 

: Finally, in the new era led by immunotherapy, how do you think you can define the treatment goals of hepatocellular carcinoma?

 

Prof. Bruno Sangro:  The goal of any treatment for a cancer patient, including liver cancer patients, is to prolong survival. We know that in liver cancer this is usually the result of multidisciplinary management. Patients who can be resected upfront may have a chance of cure, but now with immunotherapies, there is a good chance that we may increase the number of patients that we cure, and certainly we have already increased the number of patients that achieve long-term survival, even in the advanced stage.

 

来源：《国际肝病》编辑部