陈列平:抗PD-1/PD-L1抗体治疗的三大原理

2017-01-07 中美医药投资与研发联盟HIRC 中美医药投资与研发联盟HIRC

第一个原理,也是在概念上改变我们对肿瘤免疫认识的东西,叫免疫正常化,即Normalization。实际上,抗PD治疗(这里包括所有目标在于阻断这个通路的所有方法),在原理上并不是增强免疫反应,

免疫正常化 (Normalization)

第一个原理,也是在概念上改变我们对肿瘤免疫认识的东西,叫免疫正常化,即Normalization。实际上,抗PD治疗(这里包括所有目标在于阻断这个通路的所有方法),在原理上并不是增强免疫反应,而是把病人自身应该有的,但在肿瘤生长中被弱化的反应带回常态。虽然客观上我们见到了增强的免疫反应,但这才是机体对肿瘤正常的反应。就像某人借走很多的钱,久久不还,我已经不抱任何希望,突然有一天钱还回来了,我欣喜若狂,开Party庆祝等等。不过冷静下来一想,这原本就是我的钱,有什么好兴奋的呢?肿瘤免疫也是一样,我们长久以来已经认可它的无效,已经把期望值订低了。

如果以这个原理去看其他肿瘤免疫治疗方法,你就可以看出不同之处。例如,抗CTLA4抗体ipi, 就属于增加免疫反应的药,而不是Normalization。为什么这么说呢?试问肿瘤生长中,有CTLA4的过度表达或增加功能吗?没有!有CTLA4配体的功能异常吗?也没有!所以ipi的作用真的是在把免疫反应提高到比正常水平还要高的高度。高于正常的代价大家也都看到了。根据这个原理,IL2,干扰素治疗,细胞治疗,包括现在的CART治疗,在原理上都是属于这一类的,也就是把免疫反应提高到一个正常以上或正常达不到的高度。这个所谓“Maximize Immunity " 的概念,现在还是免疫治疗的“主流”方向,还有很多人在做不懈的努力。但我认为,下面5到10年的时间,这个概念会被慢慢抛弃,而免疫系统正常化的概念会逐步取而代之。

你会说,免疫正常化,但抗PD治疗也是有毒性的嘛。我的回答是,正常的免疫反应就是有毒性的,举个例,流感病毒产生了免疫反应,特异T细胞识别病毒,最终病毒消灭,这个反应很特异很正常,为什么有发烧,乏力,甚至更严重的不适呢?这些“毒性”不是因为免疫识別本身,而是免疫反应的后果。也就是说,丅细胞在识别病毒后,还会或刺激身体其他细胞放出七七八八的东西,这些东西是有毒的!比如IL-1,TNF是会引起发热的,TNF还会造成乏力的,还有IFN, IL-6等等等等。但这些毒性肯定是可控的。所以虽然是normalization, 代价还是有的!

肿瘤微环境(Micro-Environment)

我们学到的第二个原理,就是肿瘤免疫治疗需要针对肿瘤微环境,也就是局部化的治疗。

免疫学家花了无数时间,最终才搞清楚,肿瘤病人,也包括晚期垂死的病人,免疫反应全身衰竭的情况是很罕见的,就算是终期病人,血中或骨髓里都能分离到特异识別肿瘤的淋巴细胞。我做Postdoc时的老师,Dr. Hellstroms 经常提醒我这点,因为她/他们是最早做这些检测的人。換句话说,病人的免疫反应在血和骨髓中还是基本正常的(后来还有人发现肝和肺里的免疫也正常),既然全身到处都是抗肿瘤免疫,那为什么肿瘤还会长起来呢?

这个问题Steve Rosenberg 也很困惑,他明明能从血中分出抗肿瘤淋巴细胞,甚至在肿瘤里也能分到这些细胞,而且最要命的是,这些细胞在体外还真会杀死肿瘤。但外科医生就是外科医生,果断坚决,认定这些细胞就是不够,多多益善嘛,结果就有了细胞治疗的今天。

如果从normalization 的角度看,应该是哪里有缺陷就补哪里。中医说的是吃什么补什么,还是有一定的道理滴。问题是这个缺陷在哪里呢?

这里我把结论直接告诉大家:在肿瘤微环境里,不是所有的淋巴细胞都有问题的。我推测,真正的缺陷,只有那些和肿瘤细胞直接接触的淋巴细胞!可以说是免疫缺陷只有在一个很小的区域内!在这个很小的区域内,大量的免疫调节分子积聚在一起,造成一个很小范围类的免疫抑制。如何把有治疗价值的药物选择性的送到这么一个小小的地方,也就是如何把弹药送到真正的前线去,这就是现在肿瘤免疫治疗关键的也是最难的问题。现在的情况是,大量的弹药都浪费在其他无关的地方,这些弹药还不时的爆炸,引起“副作用”。

抗PD治疗做到了一部分,但还不是做的最好。因为PDL1在正常组织中还有一些,比如肺里,也有功能。这些是造成毒性的主要原因。

重建免疫反应(Resetting Immunity)

第三个原理,也是最后一个,就是重建免疫反应或者叫Resetting Immunity. 

为什么自从PD抗体治疗后,其他的免疫抑制分子靶向治疗, 比如LAG3, TIGIT, IDOi等等都没有取得很好的结果?很大原因是这些分子并没有resetting 免疫反应的作用,也就是说,靶向这些分子有可能取得免疫反应某一个阶段的改变,但并不能把整个免疫反应的方向改变过来。PD治疗后在有反应的病人上,我们可以见到肿瘤微环境中发生了戏剧性的改变:肿瘤微环境从一个充满了抑制分子和抑制细胞的“懒惰”状态逐步转变成一个免疫系统极其活跃的环境。这种改变一个分子,就会产生Chain Reaction的情况,就叫Resetting.

这个Resetting 机制还不完全清楚,也是我们最为兴趣的基础问题之一。试想有一天我们能建一方法,预测可以resetting 肿瘤免疫反应的靶子或排除不会resetting 的分子,该是多么exciting!

群员讨论摘要:

田源-元明资本

应该看看,列平教授的科学贡献应该是诺奖级的。

 

周海冰-大数投资

@田源-元明资本我的挚友在采用pdl1治疗后,肿瘤得到控制并缩小,衷心感恩列平教授,列平教授的研究成果对肿瘤治疗的贡献是里程碑级别的,期待他得诺奖的哪一天。

 

方晓骏Rick Fang 赛诺菲 波士顿

@田源-元明资本:陈教授对PD-1/PD-L1研究领域的贡献为免疫肿瘤疗法的出现开启了一扇门

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    2017-01-08 smartjoy
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    2017-01-07 1e0f770bm38(暂无匿称)

    受益匪浅!深入浅出,通俗易懂,感谢列平教授!!!

    0

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    2017-01-07 lovetcm

    陈列平有水平但不得志

    0

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    2017-01-07 天涯183

    恩,学习了

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1254905, encodeId=9d7e12549053a, content=<a href='/topic/show?id=be71139214f' target=_blank style='color:#2F92EE;'>#PD-L1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13921, encryptionId=be71139214f, topicName=PD-L1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e76f39, createdName=smartjoy, createdTime=Sun Jan 08 15:17:00 CST 2017, time=2017-01-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=168642, encodeId=be2f168642e7, content=受益匪浅!深入浅出,通俗易懂,感谢列平教授!!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=116, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b6a1943155, createdName=1e0f770bm38(暂无匿称), createdTime=Sat Jan 07 18:13:39 CST 2017, time=2017-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=168606, encodeId=a3671686067b, content=陈列平有水平但不得志, beContent=null, objectType=article, channel=null, level=null, likeNumber=73, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c4a5105539, createdName=lovetcm, createdTime=Sat Jan 07 14:17:28 CST 2017, time=2017-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=168558, encodeId=a5a9168558fe, content=恩,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=90, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Sat Jan 07 11:43:04 CST 2017, time=2017-01-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=168547, encodeId=d21216854ea5, content=文章很好,拜读受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=93, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzdAIB7UwTkHt6fQkBP8ictliaXtc5gCUmYdAW1sAETC2nhO3q6YjRHkUibyOCtP8ibmXNObTyd63A076/0, createdBy=d4111948983, createdName=1e10c84am36(暂无匿称), createdTime=Sat Jan 07 11:41:53 CST 2017, time=2017-01-07, status=1, ipAttribution=)]
    2017-01-07 1e10c84am36(暂无匿称)

    文章很好,拜读受益

    0

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