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　　随着对肿瘤免疫学的认识不断加深，临床应用不断成熟，肿瘤免疫治疗的优势也愈发被认可，一系列免疫治疗药物在不同癌症中的疗效与安全性得到临床研究的证实。本次CSCO-CAHON-SITC（9月27日下午）聚焦肿瘤领域的免疫治疗，探讨肿瘤免疫治疗的现状和未来发展。我们特别邀请该专场的两位主持肿瘤免疫治疗学会（SITC）主席美国匹兹堡大学癌症中心的Lisa H. Butterfield教授和肿瘤专家协会(CAHON)创始人之一和现任会长、美国南卡医科大学微生物及免疫系主任，郝凌斯癌症中心肿瘤免疫带头人李子海教授就肿瘤的免疫治疗进展开展一场巅峰对话！

 

　　ONCOLOGY FRONTIER: This CSCO-CAHON-SITC symposium focus on the field of tumor immunotherapy， exploring the status of cancer immunotherapy and future development， why is immunotherapy so hot? What are the changes in clinical tumors since the appearance of immunotherapy? 

 

　　P. Butterfield: I think one of the reasons that immunotherapy is considered so hot right now is because of the durability of the responses from immune-based therapies of cancer; we can get responses that last for years. ， For a lot of other therapies we are talking about a gain of weeks for patients but with immunotherapy we are talking about years. This is also without major toxicity as a side effect in many cases. 

 

　　P. Li: Good question. In terms of immunotherapy for cancer it is clearly very exciting area compared with conventional therapy such as chemo， surgery and radiation. As Dr. Butterfield just mentioned， immunotherapy could actually sort of fix the flaw or defect of the host immunity. Therefore， to have a built-in defense mechanism that is effective for not only eliminating bulky， big tumor but also to prevent relapse. So hence， immunotherapy is different from other therapies that are targeted to the cancer itself. I think we all have been laboring in the field and have seen this working in animal models for example， now we have seen this in human patients. So that is very exciting. How this has changed the clinical medicine? It has. I mean， that is the short answer. It has change what we think about cancer， it has changed the way we approach cancer. So for example， traditionally we use therapy where we push in the highest tolerated dose of chemotherapy agents， but now we have to pay attention to potential harms we do with traditional strategy to actually dampen the immune system. So this is conceptually worth thinking. Really， the immune system when we design a personalized strategy for treating cancer. So it is exciting and it has changed what we do. 

　　P. Butterfield: I think that what else is changing is that we get closer and closer to precision medicine， and that sampling the tumor to find out: if there’s PD-L1， if there are particular mutations， what the mutation load is，; these are now new biomarkers that have been developed that are helping us choose the right therapy for patients. It will be “precision medicine” soon， not quite there yet， but soon.

 

　　《肿瘤瞭望》：本次CSCO-CAHON-SITC聚焦肿瘤领域的免疫治疗，探讨肿瘤免疫治疗的现状和未来发展。为什么免疫治疗如此炙手可热？它给肿瘤学带来了哪些变化？

 

　　Butterfield博士：免疫治疗目前如此炙手可热的原因之一是因为肿瘤免疫治疗的反应持久性。一般来说，其他的肿瘤治疗方法可以使患者的生存获益增加数周，而免疫治疗则可以使患者的生存获益达到数年以上，而且很多情况下都没有出现比较明显的毒副反应。

 

　　李子海教授：与化疗、手术和放疗等常规治疗相比，肿瘤的免疫治疗给人带来很大的惊喜。正如Butterfield博士刚才提到的那样，免疫治疗实际上是针对宿主免疫系统的缺陷。建立一个内在的防御机制，不仅能够减小大块的肿瘤病灶，还可以预防肿瘤复发。因此，免疫治疗与靶向肿瘤组织本身的其他疗法不同，它主要是针对整个机体进行调节。目前很多肿瘤工作者都在致力于免疫治疗的研究，并且已经在很多动物模型中验证了免疫治疗的作用，而且现在在患者身上我们也已经实实在在地看到了它的疗效，这一点非常令人兴奋。谈到免疫治疗对于肿瘤学的影响，我认为它改变了我们对于肿瘤的认识以及治疗肿瘤的方式。例如，以前我们选择化疗药物的原则是推荐安全性最好的药物，但如今则更强调避免传统化疗药物对于免疫系统的潜在抑制作用。因此，在制定个性化的肿瘤治疗策略时，我们必须考虑到机体免疫系统的作用，这就是免疫治疗带来的主要变化。

 

　　Butterfield博士：免疫治疗的突出影响之一就是使我们越来越接近精准医学，例如通过对肿瘤样本的分析，我们可以确定患者是否有PD-L1或者其他的基因突变以及突变的负荷等，这些正在开发的新生物标志物将在不久的将来帮助我们为患者选择更为精准的治疗方法。

 

　　ONCOLOGY FRONTIER: Since immunotherapy has made surprising effects in the field of melanoma， many related studies have been carried out in many kinds of cancers. What are the outstanding achievements of tumor immunotherapy in your research area? What is the direction of immunotherapy in the future? 

 

　　P. Butterfield: I work in melanoma and hepatocellular cancer， and I think what we’ve done in melanoma successfully for many years and what we’re now building onto with checkpoint blockade and with other new combinations， is being translated to hepatocellular cancer and other tumor settings. In hepatocellular cancer we don’t yet have the successes. Still， even the more limited success of checkpoint blockade and HCC is much more exciting than perhaps something like sorafenib where again we are talking about weeks of increased survival. In our research we are now thinking about the immune effects in HCC and in other tumor types that are not traditionally thought of as responsive to immunotherapy. We are looking at mechanisms， then we are going to start to combine the right things. In lung cancer we had an early hit because of all the mutations， but in the other tumor types like HCC that are less responsive， it’s the combinations and translating from the successful tumors to the others that will get us where we need to be. 

 

　　P. Li: Yeah， I think maybe is a misconception that only melanoma or renal cell cancer are immutable to immunotherapy. The reason I am saying this is that the host immune system is a wired， hard-wired to deal with transformed cells. In some cancer type we do see better response to， for example PD-1 agent but the other type of cancer we may need to find some other switches to turn on or off to make immune system work better. One other thing is important， for example， even with PD1 agents now it has been shown to be really a game changer for a variety of cancer types. Actually， just this past week USFD has approved pembrolizumab for the treatment of gastric cancer， a big problem in China. Also， nivolumab actually for hepatocellular carcinoma regardless of PD-L1 status. So the point is that immunotherapy should not be restricted to particular histological type of cancer. In terms of what do we do， both Dr. Butterfield and myself， we are basic immunologist. The last last questions still in a feud， we don’t have answer yet. For example， we don’t really know how to turn off one of the major immune regulatory mechanism called regulatory T-cells. We don’t know how to combine PD1 agents with other type of the immune therapy， such as cytokine based strategy， such as cellular therapy and so on. We don’t even know what other principles for immune recognition and tolerance completely yet. So we have a lot of work to do and one of the things I want to leave to you is that if you are excited about immunotherapy today， you’ll be more excited tomorrow. 

 

　　《肿瘤瞭望》：自从免疫治疗在黑色素瘤领域取得令人惊喜的效果以来，它在许多癌种中都开展了许多相关的研究。目前肿瘤免疫治疗取得的突出成绩主要有哪些？还存在哪些挑战？

 

　　Butterfield博士：我主要从事黑色素瘤和肝细胞癌的研究，在黑色素瘤方面免疫治疗的成功已经实现了许多年，现在我们正在试图将免疫检查点抑制剂所取得的成功经验扩展到肝细胞癌等其他肿瘤领域。虽然免疫检查点抑制剂在肝细胞癌中所取得的成功比较有限，但是跟索拉非尼等靶向药物所取得的几周生存获益相比，还是很令人鼓舞的。我们现在正在试图通过联合一些其他的机制增强肝癌和其他等对免疫治疗不敏感的肿瘤的免疫效应。由于肺癌的高突变负荷，免疫治疗的疗效很明显。然而在对免疫治疗不敏感的肝细胞癌等其他肿瘤类型中，联合治疗以及借鉴从免疫治疗中取得成功的其他肿瘤的治疗经验将是很好的一个方向。

 

　　李子海教授：我想人们普遍存在一个误解，那就是认为只有黑色素瘤或肾细胞癌对于免疫治疗是敏感的。实际上宿主的免疫系统与肿瘤细胞之间存在普遍关联。某些癌症类型确实对PD-1药物更为敏感，而其他的肿瘤则可能需要寻找更好的靶点“开关”从而使免疫系统更好地发挥作用。而且即使是PD-1抑制剂也已经被证明能够在多种肿瘤类型中起效。实际上就在上个星期，US FDA已经批准pembrolizumab用以治疗胃癌。此外，nivolumab在肝细胞癌中也具有一定的疗效，也已被US FDA二线批准，且无论PD-L1状态如何。因此重点是，免疫治疗不应该仅局限于某些组织学类型的肿瘤。然而肿瘤免疫治疗还有许多有待探索的领域，例如，我们还不知道如何关闭主要免疫调节机制之一的调节性T细胞以及如何将PD-1药物与如基于细胞因子的治疗策略或细胞治疗等其他类型的免疫治疗相组合。我们甚至不清楚其他的免疫识别和耐受机制等。因此，我们要做的工作还有很多，然而可以肯定的是，肿瘤免疫治疗的前景一定是光明而灿烂的！

 

　　ONCOLOGY FRONTIER: Screening the patients who are sensitive to immunotherapy is key to improve its efficacy， what are the current biomarkers that can help us to guide the tumor immunotherapy?

 

　　P. Butterfield: I think the biomarker that we are learning how to use is the PD-L1 staining in tumor， which is informative， but we still have several different antibodies and assyas， and we are trying to work out how the results of one test for one drug can relate to being able to get the second drug for a patient. Mutation burden， this is also something that we’re working on in the field， it is only available in certain places and it is done very differently between groups. So， I think we have important signals， including myeloid-derived suppressor cells， mutation burden， PD-L1， that we need to standardize and make broadly available. And then back to the bench， the immune profiling of RNA， DNA， and proteins in the tumors and the blood that will get us to that next leap forward. We are making strides， but we have some good work ahead of us yet. 

 

　　P. Li:  There is also something called immune-cancer circle， so in other words to get the immune system going you have to recognize something in the tumor， you have to activate it the immune system. The immune system somehow has to find the way to go to the tumor， and then in the tumor it has to stay there and be effective in killing those tumor cells. Now you can imagine， every single step of this circle could go wrong， so knowing that it is not surprising that what works for one patient may not work for the other simply because the defect， the precise defect of the immune system might be different between those two individuals. So therefore， yes， we are strong advocates for bio-marker driven selection of immuno-oncology agents for treatment of cancer patients. As Dr. Butterfield just mentioned， the more we know about the immune profiling of the cancer， the more we know about the mutation status， the more we know about the target of a particular agent， then we will be able to tailor treatment to a particular patient and therefore， to actually improve the rate of responsiveness and hopefully a cure. 

 

　　《肿瘤瞭望》：筛选对免疫治疗敏感的优势人群是提高肿瘤免疫治疗疗效的关键，哪些生物标志物可以用于指导肿瘤的免疫治疗？

 

　　Butterfield博士：目前正在使用的生物标志物毫无疑问是肿瘤表面的PD-L1，这是比较有说服力的一个，但我们还在进行一些其他的探索，例如我们正在努力研究将某种药物的检测靶点用于指导第二种药物的治疗。另外，骨髓源性抑制细胞、突变负担、PD-L1的规范化和广泛化使用也是重要的研究方向。肿瘤和血液中的RNA、DNA和蛋白质的免疫分析也将使我们进入下一个飞跃。虽然我们已经有了很大的进展，然而未来要做的工作还有很多。

 

　　李子海教授：现在有一个名词叫做肿瘤免疫环，换句话说，要使免疫系统发挥作用，你必须先识别肿瘤，然后再进一步激活免疫系统。免疫系统以某种方式寻找到通往肿瘤细胞的途径，发现并有效杀死肿瘤细胞。我们可以想象，这个环中间的任何一个步骤都有可能出错，所以对某一个患者有效的免疫治疗可能并不适用于另一个患者，这一点也不奇怪，因为两个人的免疫系统缺陷可能完全不同。因此，我们强烈倡导根据生物标志物指导肿瘤患者的免疫治疗。正如Butterfield博士所说，我们对肿瘤的免疫分子谱以及突变状态了解得越多，我们对特殊药物的靶点就了解得越多，那么我们就能够制定个体化的治疗策略，从而提高药物的疗效，并有望使患者达到治愈。