EASL专访丨Bruno Sangro：肝细胞癌免疫治疗最新进展

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。

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.

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<Hepatology Digest>: 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.