[CSCO2017巅峰对话]Fred Hirsch &周彩存:回顾与展望PD-1/PD-L1肿瘤免疫治疗

作者:肿瘤瞭望   日期:2017/10/11 14:29:47  浏览量:29719

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肿瘤瞭望:肿瘤免疫治疗一度被许多人视为攻克癌症的新希望。2013年美国《纽约时报》和《科学》杂志将肿瘤免疫治疗评为“重大突破”。大多数人对肿瘤免疫或者PD-1的认识可能仅仅是PD-1抑制剂是一种新型抗肿瘤的药物,或者PD-1曾经治愈美国卡特总统的黑色素瘤。2017CSCO大会期间《肿瘤瞭望》有幸邀请了科罗拉多州立大学癌症中心副主任Fred Hirsch教授和上海市肺科医院肿瘤科主任周存彩教授,从PD-1抑制剂的作用机制到肺癌领域的研究和应用进展,以及双方合作成果和愿景等方面进行了精彩的对话交流。

Interview with Professors Fred and Zhou

Mechanisms of  PD-1/PD-L1 checkpoint treatment

 

Dr. Fred: Well, that is a very complicated process. What we are talking about here is that the cancer is recognized as a foreign body and, of course, the immune system will try to fight it. However, the cancer is very smart and the cancer will try to escape from the immune system through very, very complicated mechanisms. The T cell lymphocytes play a major role in the fight against cancer—the immune system fighting the cancer. And, of course, what we are leveraging on—in terms of immunotherapy today—is the connection between the receptors on the cancer cell and the connection to receptors on the T cells. PDL-1 is the receptor on the cancer cell. PD-1 is a receptor on the T lymphocyte. When they go together, as loving partners, that actually leads to a suppression of the T lymphocytes. That is not what we want. We want to stimulate the T lymphocyte and the immune system; we don’t want to suppress it. So, what the drugs do is actually to cut the connection between the T cell receptor and the receptor on the cancer cell. And if you do that, you cut the suppressor effect of the receptor and, instead, you stimulate the T cell lymphocyte. And that is what we want. And that is where the encouraging results have come so far.

 

Now, I have to say this is very simplified. And this is just one mechanism in a very complex system. There are a lot of other cells playing a role. There are a lot of other receptors playing a role. There are also what we call cytokines, which are in some senses at least in the immune process. So, we need to learn much more about those processes. But believe me, in the future, there will be drugs which target other mechanisms—not only the PD-L1 and PD-1, which we are currently talking about. So, in my opinion, we are only on the tip of the iceberg in terms of understanding and in terms of immunotherapy treatments. But, it is very, very encouraging what we have seen so far.

 

Dr. Zhou: Yes, I agree. The PD-1 and PD-L1 signaling pathways play an important role in the immune escape for the solid tumor. The binding of the PD-L1 to PD-1 will produce energy for the T cells. That means the T cells have lots of functions to kill the cancer cells. So, usually, PD-1 and PD-L1 inhibitors work in the solid tumor in the second line—maybe in the first line. Actually, immunocheckpoints—there are many right? PD-1 and PD-L1 are just one of them. We have LAG3, TIM-3. How about immunocheckpoints in the future for treatment of cancer?

 

Dr. Fred: And there are drugs already developed against other checkpoints, so we will see much more of those results in clinical studies in the years to come. That’s for sure.

 

Combinations of PD-1/PD-L1 and others

 

Dr. Zhou: Okay. So how about a combination of PD-1 inhibitors as immunocheckpoint inhibitors? It could increase the efficacy of immunotherapy in solid tumors.

 

Dr. Fred: Yes, I agree with you. Synergy between immunotherapy combinations—I think we are starting to learn something about it. We have clinical trials, also, with CTLA-4 inhibitors and PD-L1/PD-1 inhibitors and we will see other combinations. I will make a personal comment and that is that these days, the drug companies are lounging. Many, many, many combination studies—it can be combinations with other immunotherapies; it can be combinations between immunotherapy and chemotherapy; it can be combinations between immunotherapy and targeted therapy—in my personal opinion, a lot of large studies are lounged without sufficient scientific background.

 

 Dr. Fred: We don’t know exactly the science behind those combinations. Should those combinations be given concomitantly? Should they be given sequentially? We lack this type of information, in my opinion, and hopefully in the future, we will see some smaller studies which also can have a clear scientific approach—not only just a clinical efficacy approach.

 

Dr. Zhou: Yeah, I agree, you know because this area is very hard. The pharmaceutical industry could lose in this area. They just try to move to get a lead. That’s what they do, right?

 

Dr. Fred: And the safety profile could be an issue, particularly when you combine (Immune Oncology, IO) I-O with I-O. We know that this combination can give quite a serious toxicity. We might overcome that in the future with dose modifications and schedule modifications, but that is something we’ll need to work out.

 

Dr. Zhou: Right. And that’s why the combination IPI and nivolumab works in non-small cell cancer. At first, the combination is intolerable in most cases. Now we know that the dose of IPI is important in terms of toxicity. When we decrease the dose of IPI, that combination works in non-small cell lung cancer.

 

Dr. Zhou: I agree. We know that PD-1 expression is important. We also know that immunoscore is important. Now, we know some data about tumor mutation burden, neoantigen. We don’t know which biomarker is more important in predicting efficacy of immunotherapy. We need to study. Neoadjuvant immunotherapy is one of the best ways to solve such kinds of problems.

 

Dr. Fred: Well, in first line therapy, pembrolizumab is approved with PD-L1 with defined cut off. Nivolumab is not approved in first line therapy; it is approved for second line therapy. So, it depends on the clinical situation. In first line therapy, pembrolizumab is the answer. For second line therapy—particularly for those patients who have not received immunotherapy in first line—you have some choices. No, I would hope that we would better understand the predictive biomarkers, because I think that we can agree that these therapies are not cheap; they are expensive therapies, and at this stage, only a certain subgroup of patients will benefit from it (about 20 percent of the patients). So, I think, for many reasons—also financial reasons—it is important to find the right selection of patients for these therapies.

 

Dr. Zhou: Right, I understand. How about a combination of I-O and chemotherapy? We have the KEYNOTE-021 trial. G panel, right? Which was published in ASCO and also in ESMO. You know, the combination of pembro plus Alimta carbo produced significant improvement in the tumor response rate as well as in progression-free survival. You know, median progression-free survival is about 19 months. It’s unbelievable, you know.

 

Dr. Fred: Right. My comment to that is it is a randomized Phase II study, and there is a Phase III trial ongoing. We haven’t seen results from the Phase III trial.

 

Dr. Zhou: Maybe at the next ASCO.

 

Dr. Fred: It could be. So, I certainly hope these results will be validated in the Phase III setting. But, in my opinion, we need to see the Phase III data. And another thing, I would like to see all the PD-L1 studies as relates to outcomes. We haven’t seen that yet either.

 

Prediction of anti-PD-1 treatments

 

Dr Fred: One area where we have a focus, currently, in the US and in our institution is the neoadjuvant approach. And the neoadjuvant approach gives us an opportunity to study the scientific molecular background for treatment response, treatment assistance, and I think this knowledge will be very important in the future treatment planning.

 

Dr. Zhou: Yeah, right. So, we just talked about a neoadjuvant study of nivolumab in the adjuvant setting, right? So actually, in that study—a very small sample sized study in which about 22 patients were enrolled into the trial—were given neoadjuvant nivolumab. The cystic tumor response rate was about 22 percent—not so high. When we look at the pathological response, it’s quite good. Many, many patients developed a kind of tumor shrinkage, even major tumor swing-age. So, I think that maybe resisting graft earlier is not good enough for immunotherapy, right?

 

Dr. Fred: Right. And I agree with you. I think we need to look more into the definition of a “response.” To that end, I can tell you that the organization I represent, the ISOC, will be holding a workshop with the FDA in the beginning of 2018, where we will look into neoadjuvant therapies and we will discuss what will be the right trial designs, what will be the definition of responses. And I think we need to revisit the whole resist criteria—not only for immunotherapy, but also for targeted therapies, for TKIs.

 

Collaborations between CHN and US

 

Dr. Zhou:  So, in China, I’m leading a randomized Phase III trial comparing Chinese PD-1 inhibitor plus Alimta carbo versus Alimta carbo in the Chinese population. So, the study was studied a few months ago. About 60 patients were included in the study. We hope to get the results at the end of next year. This is the Chinese KEYNOTE trial.

Dr. Fred: Very exciting. Do you do PD-L1 studies as well?

Dr. Zhou: Yeah, we will, we will do that. We have two primary points: progression-free survival in the IT population and also, in the PD-L1-positive population.

Dr. Fred: Right. That is the beauty with international collaboration.

Dr. Zhou: We work together.

Dr. Fred: Dr. Zhou’s department and my laboratory is working closely together on many biomarker studies.

Dr. Zhou: Right, right.

Dr. Zhou: I’m happy to work with him. We have worked together for many years.

 

So, I asked you about tumor mutation burden. As we talked a few months ago, you know, the Chinese pharmaceutical industry asked to meet you to discuss the possibility of doing the trial—the TMB-driven study. Is it possible or not?

 

Dr. Fred: Yeah, I am a little bit skeptical about the tumor mutation burden as a predictive biomarker over a couple of reasons (which I mentioned in my presentation today). One is that there is no standardization of a tumor mutation burden. What should be the sequencing? What is the definition of a high tumor mutation burden? How many genes should be covered? There are several open questions around that. Secondly, we are using two more mutations as a generic term. I think we will learn more and more about differences between mutations. All mutations are not equal. Some are more immunogenic than others, so I think, we will need to learn more about that. So, that makes me a little bit skeptical with the use of tumor mutation burden as of right now.

 

Dr. Zhou: Okay, I agree. We will try to do a small sample size Phase II trial based upon the mutation burden. We use the target NGS panel and also WES—NGS as control.

 

Dr. Fred: There were interesting presentations at ESMO this year, where they looked into tumor mutation burdens based on plasma. And interesting data came out when they applied it to the OAK study with atezolizumab. So, I think, mutation burden as a predictive biomarker needs much more validation and much more standardization.

 

Dr. Zhou: I agree. In that study, they used Foundation Medicine to detect the TMB. You know, Foundation Medicine is just the panel test, not Hujilong. Sequencing, right?

 

Dr. Fred: But Foundation Medicine is one company. There are several other companies using different platforms, different definitions, and so on.

 

Dr. Zhou: Especially in China. We have over 200 NGS based companies. Each NGS uses a different platform. That’s our problem. We need standardization.

 

Dr. Fred: Yeah, I don’t know any around clinical trials—I would think there are collaborative clinical trials. As I mentioned before, Professor Zhou’s department and my laboratory are collaborating on biomarker development and biomarker validation. And that is a collaboration which has been very successful for many years. This type of collaboration is important. I think, both institutions bring a lot to the table and synergize.

 

Dr. Zhou: So, actually, the preface host—he gave us a lot of help. You know, he took two of my doctors to be trained at his lab. That’s very important. He gave us a lot of contributions, you know. So, I think in the near future, we can work together more in immunotherapy. Now, we have so many trials from the Western (US) pharmaceutical industry performed in China. Maybe in the near future, the Chinese pharmaceutical industry will do the chemical trials in the United States. They also need your help. That’s very important, right?

 
 
 
肿瘤免疫逃逸机制与检查点抑制药物
 
Fred Hirsch教授:PD-1通路抑制剂的工作机制十分复杂,我们可以简单认识一下此过程。首先,正常情况下肿瘤细胞的抗原可以被免疫系统T细胞表面受体识别并产生杀伤清除作用,而肿瘤细胞很狡猾,可通过表达PD-L1蛋白与T细胞表面的PD-1结合,诱导T细胞凋亡、抑制T细胞的活化和增殖,从而逃脱免疫的杀伤作用。这种免疫逃逸是肿瘤迅速增殖的原因之一。
 
PD-1抑制剂就是要阻断肿瘤细胞PD-L1和T细胞PD-1的结合,恢复人体T细胞对肿瘤的识别和杀伤作用。当然这仅仅是简单的作用机制介绍,实际上肿瘤和T细胞之间的识别和相互作用非常复杂的,PD-1/PD-L1的具体识别和相互作用过程还涉及到许多复杂的分子信号蛋白作用,我们需要有更深入的研究去阐明肿瘤的免疫逃逸机制,将来也会研发出更多的、作用于其他靶点的肿瘤免疫抑制药物。
 
虽然我们才刚刚拉开认识肿瘤免疫机制、开展肿瘤免疫抑制治疗的序幕,但这仍然是一个鼓舞人心的开始。
 
周彩存教授:我同意您的看法。在实体肿瘤中,PD-1/PD-L1使免疫系统丧失监视和抑制肿瘤的作用,是肿瘤发生免疫逃逸的重要机制。而PD-1/PD-L1仅是肿瘤免疫检查点阻断中的一种机制,目前肿瘤免疫检查点抑制还包括LAG-3、TIM-3等众多作用靶点。您如何看待免疫检查点抑制在肿瘤治疗中的应用前景?
 
Fred Hirsch教授:确实还有很多的肿瘤免疫检查点抑制的治疗方法正在研究当中,我们也将会看到越来越多的关于肿瘤免疫检查点抑制治疗的临床研究,这将是很有应用前景的研究方向。
 
PD-1抑制剂联合用药
 
周彩存教授:PD-1抑制剂和其他的肿瘤免疫检查点抑制剂联合应用是否可以增加肿瘤免疫治疗的效果呢?
 
Fred Hirsch教授:关于联合应用肿瘤免疫抑制剂的临床研究已经有所报道,比如CTLA-4抑制剂联合PD-1/PD-L1抑制剂。目前许多医药公司开展了众多的药物联合应用的临床研究,包括各种肿瘤免疫抑制剂之间,肿瘤免疫抑制剂和化疗药、分子靶向治疗药等联合应用。但我们并不了解这种药物联合作用背后的科学机制。所谓的联合用药究竟是指同时用药,还是序贯用药?期待能有更多的基础研究来阐述联合用药的科学依据。
 
另外一方面,药物的安全性也是我们关注的焦点,尤其是肿瘤免疫治疗药物之间的联合应用可能会增加药物的毒副作用。我们仍然需要通过调整药物剂量、疗程等研究,进一步克服和解决这些问题。
 
周彩存教授:在“N+I”(Ipilimumab联合Nivolumab)治疗非小细胞肺癌(NSCLC)的研究中,多数患者于治疗初期无法耐受联合用药,当IPI减量后这种联合治疗才发挥了效应。提示未调整IPI(Ipilimumab)用药剂量可能增加毒副作用。
 
在ESMO和ASCO大会中也可看到“Pembrolizumab联合培美曲塞+卡铂用于晚期NSCLC患者治疗”的报道(KEYNOTE-021)。结果显示免疫抑制剂联合化疗较对照组单用化疗显着的提高了客观缓解率(Objective Response Rate,ORR),并延长了无进展生存(Progress Free Survival,PFS)时间。Pembrolizumab联合两药化疗的ORR高达55%,确实是非常不俗的治疗效果。
 
我们知道FDA批准上市的PD-1/PD-L1抑制剂多达数种,比如Pembrolizumab 和Nivolumab,在贵国临床应用中哪一类的PD-1/PD-L1抑制剂更受青睐?
 
Fred Hirsch教授: 目前Pembrolizumab (Keytruda)主要用于PD-L1高表达(>50%)的NSCLC一线治疗,而Nivolumab主要用于二线治疗,因此需要根据患者的具体病情来选择PD-1/PD-L1抑制剂。当然,我们不能否认的是肿瘤免疫抑制剂的费用比较昂贵,且所有肿瘤患者的应答率仅为20%左右。因此,我们希望能获得更多的、有效的生物预测标志物来筛选可以从肿瘤免疫抑制治疗中获益的人群。
 
PD-1/PD-L1抑制剂的生物预测指标
 
Fred Hirsch教授:我们比较关注的另一个焦点是肿瘤免疫新辅助治疗。新辅助治疗可为进一步明确肿瘤的分子背景、治疗应答和抵抗等科学机制提供活体环境,这些研究机制的厘清将为肿瘤免疫治疗计划的制定提供极大的帮助。
 
周彩存教授:目前我们知道PD-L1表达水平对肿瘤免疫治疗的预测具有重要价值。此外,免疫评分(immunoscore)也有很大的潜力,我们也看到了一些关于肿瘤突变负荷(Tumor Mutation Burden, TMB)、微卫星高度不稳定(microsatellite instability-high, MSI-H)、错配基因修复缺失(mismatch-repair deficiency,MMR)以及突变相关新抗原(mutation-associated neoantigen)等具有潜在价值的生物预测方法。究竟什么样的生物标志物在肿瘤免疫治疗效价的预测中更有价值,我认为新辅助免疫治疗是解决这个问题的重要研究方法之一。
 
此外,在nivolumab新辅助免疫治疗的研究中(NCT02259621),共有22例患者患者入组。研究结果显示肿瘤应答率仅有22%,但病理缓解率高达43%。这提示可能存在削弱免疫治疗效果的抵抗物。
 
Fred Hirsch教授: 我认为应该进一步明确肿瘤免疫治疗“应答”的定义(Definition of Responses)。我所服务的国际肺癌研究协会(IASLC)也将在2018年初与FDA协作,进行新辅助肿瘤免疫治疗的研究。我们不仅会讨论合理的研究设计方法,还将制定有关肿瘤免疫治疗“应答”的定义。同时我们需要回顾包括PD-1/PD-L1免疫治疗、TKI靶向治疗等所有药物治疗抵抗的标准(Resisting Criteria)。
 
今年ESMO公布了一些很有意思的研究,来自美国的David R. Candara教授汇报了肿瘤免疫治疗相关血液生物标志物检测,即二线及以上NSCLC治疗血液肿瘤突变负荷与Atezolizumab疗效提高的相关性研究(POPLAR和OAK)。我认为TMB作为生物预测标志需要更多的此类临床和基础研究确认。
 
肿瘤免疫治疗研究的国际合作,中国不能缺席
 
周彩存教授:我在国内牵头进行了一项随机、前瞻性Ⅲ期临床试验——“PD-1单抗+培美曲赛+卡铂”对比“培美曲赛+卡铂”一线治疗非鳞非小细胞肺癌。这项研究在几个月前已经开始,大约有60例患者入组。我们希望年底可以获得一些研究成果。这是属于中国本土的KEYNOTE临床研究,希望研究数据能为中国患者的治疗提供指导。
 
Fred Hirsch教授:这是非常值得期待的研究,那您的研究中会涉及PD-L1的相关分析吗?
 
周彩存教授:是的,我们会涉及到PD-L1阳性表达人群的无进展生存期分析。
 
Fred Hirsch教授:这正是国际合作的魅力所在。
 
周彩存教授:希望我们可以有更多深入的合作。
 
Fred Hirsch教授:周教授的科室和我们的实验室之间在分析标志物方面已有许多紧密的合作。
 
周彩存教授:很荣幸多年来能与您开展研究合作。几个月前我也和您提到了关于TMB的研究,我们国内也有一些研究机构想和您讨论一下TMB驱动的研究,不知道是否可行?
 
Fred Hirsch教授:我对TMB作为生物预测指标存在几点疑惑,这在我今天的CSCO演讲中也提及到。一是缺乏判定TMB 的标准。哪些基因需要进行测序?TMB的定义是什么?这是都是存在争议的问题。二是我们将会发现在各种突变之间存在更多的区别,且所有的突变并非一致的,有些突变的免疫原性可以更显著。因此,目前使用TMB进行肿瘤免疫治疗生物预测还缺乏比较可靠的支持证据。
 
周彩存教授:我同意您的看法,所以我们也将进行一些小样本的TMB相关Ⅱ期试验。我们将使用二代测序靶向测序包(NGS panle)进行检测,同时利用二代测序的全外显子检测(WES-NGS)作为对照。
 
Fred Hirsch教授:虽然我对中国的临床试验并不熟稔,但我相信我们将会有越来越多的研究合作机会。如前所述,我们实验室和周教授科室间的合作主要在生物标志物的发现和验证方面,这已经是多年来非常成功的合作。这种合作对双方均会产生众多的、令人瞩目的研究成果。
 
周彩存教授:Fred Hirsch教授您给予我们非常多的帮助,我们科已经有2位医生在您的实验室中进行研究和培训。我想在不远的将来我们会在肿瘤免疫治疗方面有更多的合作机会。目前有很多西方国家的医药企业正在中国进行临床药物试验,未来中国的医药企业也同样可以在美国进行药物临床研究,他们也需要贵国同道的帮助。感谢您接受此次采访以及一直以来的支持,希望您在厦门过得愉快。
 
专家简介
 
Fred R. Hirsch 教授
科罗拉州立大学医学院、肿瘤内科学系医学和病理学教授
科罗拉多州立大学癌症中心副主任、国际项目负责人
国际肺癌研究协会(IASLC)执行主席
美国癌症研究协会(AACR)临床试验委员会委员
世界卫生组织(WHO)肺肿瘤分类制定专家
 
周彩存 教授
主任医师,医学博士,博士生导师
同济大学医学院肿瘤研究所所长,肿瘤学系主任
上海市肺科医院肿瘤科主任
国际肺癌研究协会(IASLC)教育委员会委员
中国抗癌协会肺癌专业委员会常委
中国抗癌协会临床肿瘤学协作中心执委会委员
《Lung cancer》副主编,《Translational lung cancer research》主编

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CSCO周彩存

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