以身试药--诺贝尔奖获得者拉尔夫•斯坦曼对癌症免疫治疗的最后探索

简介：在1973年发现了新型免疫细胞树突状细胞之后，拉尔夫·斯坦曼用很长时间来证明这种细胞在人体抵抗病原体中发挥的重要性，以及它如何被用来治疗疾病。34年后，他寄望于这种细胞能拯救自己的生命。通过与全世界科学家合作，他基于树突状细胞设计了一系列癌症治疗方案。

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2011年，拉尔夫·斯坦曼因发现树突细胞及其在获得性免疫中的作用”而获得诺贝尔生理学或医学奖。同时，他也用自己研发的树突细胞疗法治疗自己的恶性胰腺癌，将生命由预期的数月延长到四年。

树突状细胞——因其形似树枝状的突起而得名——通过编程其他细胞来指挥和调动人体免疫系统识别和摧毁入侵者。在纽约洛克菲勒大学任职的生理学家斯坦曼，试图用基于树突状细胞的疫苗预防慢性感染，如HIV，结核以及癌症治疗。因此当他在2007年3月份被诊断出患胰腺癌晚期时，他很自然的寄希望于他穷尽毕生精力研究的树突状细胞上。通过与全世界科学家合作，他基于树突状细胞设计了一系列癌症治疗方案。

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红色的树突细胞将抗原呈递给蓝色的淋巴细胞，使其识别杀灭癌细胞

“他将自己当做实验对象，并希望实验结果能为各种相关研究带来益处。他希望能拯救自己，也将这看做一个难得的学习机会，”伊拉·梅尔曼(Ira Mellman)说。梅尔曼是南旧金山基因泰克公司肿瘤研究部的副主席，他同时帮助斯坦曼设计治疗方案。

2011年10月3号，斯坦曼因其研究成果共同分享了诺贝尔生理及医学奖，但他永远不会知道这个消息了。在68岁这一年，与癌症斗争了4年半之后，他在诺贝尔奖揭晓的3天前病逝。

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与癌症做斗争

科学家们制定了一个计划：诺森斯威治将拿走一部分手术后的肿瘤组织，在小鼠体内培养获得足够的实验材料;梅尔曼负责培养出一个细胞系用于检测肿瘤对药物的敏感性;多伦多的一个合作者将对肿瘤细胞进行测序以期找出一种可以提供药物可选择性的突变;德国的合作者将提取并合成肿瘤表面的多肽，用于疫苗实验。而在治疗方案上，斯坦曼采用的是以传统化疗结合多种对其肿瘤有意义的实验性疗法。

斯坦曼一共尝试了8种实验性疗法，每次尝试一种实验，这些单一样本，特许使用的治疗方案都提交FDA并获得准许。癌症之所以具有致命性的一个原因是它通过不同的策略来逃避免疫细胞的识别和杀伤。因此斯坦曼设计出了基于树突状细胞的三种疫苗做自体实验。最终，他研发出一种疫苗，试图先使用斯坦曼的肿瘤表面特异性多肽刺激斯坦曼自己的树突状细胞，然后用激活的树突状细胞启动免疫应答。当这些树突状细胞注射回体内时，已经可以识别并攻击肿瘤细胞了。

癌症疫苗的原理

“这是个体化医疗的终极案例，”斯坦曼的合作者，纽约斯隆-凯德琳癌症纪念研究中心的肿瘤专家杰德·沃尔乔克(JeddWolchok)说。但这远没有达到斯坦曼的要求。他和免疫领域的其他专家都认为，这些疫苗如果与一种临界点-阻断抑制剂同时使用会效果更好，其能将被肿瘤抑制的免疫系统恢复至全盛状态。斯坦曼认为，这种联合施用会对肿瘤细胞起到连续打击的效果。他单独使用了抑制剂ipilimumab，但没有与其他治疗同时进行。这是因为联合用药的临床试验需要获得审查人员、药品制造商和FDA的共同准许，但斯坦曼和他的团队没有获得任何批准。Ipilimumab在2011年3月获得FDA的批准用于黑色素瘤的治疗，而与树突状细胞疫苗的联合治疗试验才刚刚开始在黑色素瘤和肾细胞癌患者中进行。

我们无法得知哪种治疗方案延长了斯坦曼的生命。他的存活时间比最初的预计要长——像他这样的胰腺癌患者存活时间一般是几周到几个月。“拉尔夫坚信他的树突状细胞延长了自己的生命，”施莱辛格说，“树突状细胞肯定起了一定的作用，但我觉得我们永远不会知道具体的原因。”虽然没有对照组，斯坦曼的单一样本试验还是推动了整个领域的发展。

如今，科学家们已研发出免疫抑制剂（PD-1）+树突细胞疫苗两大尖端免疫疗法联合的疗法，这种通过扩增树突细胞活化免疫，同时联合PD-1解除癌细胞对免疫细胞的刹车机制，最大限度激发人体自身免疫来攻击癌细胞的联合疗法已经开始对患者进行临床治疗，前景非常值得期待！

案例一

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案例二

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