THE 2018 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE WINNERS

THE 2018 NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE WINNER

The University of Texas at MD Anderson Cancer Center

Houston, TX

The Texas T Cell Mechanic

James Allison, Ph.D., knows his T cells. For the past 30 years, he''s studied them inside and out, learning what makes them run and hum. From his laboratory have emerged some of the most important discoveries in immunology.

In the early 1980s, Allison was one of the first to identify the T cell receptor—the part of a T cell that binds to antigen and functions as the T cell’s ignition switch. A few years later, in 1992, he showed that a molecule called CD28 functions as the T cell’s gas pedal. Then, in 1995, when no one else was even thinking there would be such a thing, he identified the T cell''s brakes, in the process opening up a whole new vista in cancer treatment.

Known as checkpoint blockade, the treatment approach uses antibodies to block the action of this braking molecule, called CTLA-4. By “taking the brakes off” the immune response, the treatment enables a more powerful anti-cancer response.

Some of the most dramatic clinical responses seen in recent years have occurred with checkpoint blockade antibodies, including ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). Fittingly, in 2013, Science magazine named cancer immunotherapy the “breakthrough of the year,” citing Allison’s work in particular.

Allison is currently chairman of immunology at The University of Texas MD Anderson Cancer Center in Houston, Texas. He serves as director of CRI’s Scientific Advisory Council, a position he assumed in 2011, when Lloyd J. Old, M.D., retired (pictured together on right).

For such a high-powered scientist, Allison is surprisingly down-to-earth. He speaks in the drawl of his native Texas, enjoys a good BBQ, and plays harmonica in a garage band called "The Checkpoints," composed of other immunologists.

We spoke to Dr. Allison about his research, his love of science, and his hopes for the future of cancer treatment.

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CRI: What’s the advantage of immunotherapy over other cancer therapies?
Dr. Allison: It''s compelling to think of the immune system in cancer for three reasons. One is the incredible specificity of the immune system. Because cancer cells have distinct targets, the immune system can target those cancer cells specifically, and with very few of the side effects normally associated with conventional drugs.

The second one is that the immune system can adapt as the tumor changes. The immune system, if you keep stimulating it in the proper way, can change as the tumor changes. 

The third one is that you can get memory and that''s the hallmark of the immune system that doesn''t exist for any other type of cancer therapy. Once you''ve generated T cells that can recognize cancer, you''ve got them basically for the rest of your life. Whereas with every other drug, they kill a bunch of tumor cells and then the drugs go away.

Also, you won''t find the phenomenon of resistance with immune-based therapies. If the tumor comes back, you can treat it anti-CTLA-4 again, and again, and again. It never quits working.

CRI: How did you get into science?
Dr. Allison: My father was a doctor. I grew up in a very small town in south Texas and I guess from him I got an interest in medicine and then that led me to have an interest in science. And I was lucky enough in the eighth grade to go to Austin, Texas and participate in a science course there for high-level students. After that, I just knew I wanted to do science. And then later that grew into immunology. I became interested in cancer because I''ve lost a number of family members to cancer. My mother and two of her brothers, and my own brother died of cancer.

CRI: You’re known for your work on ipilimumab, the anti-CTLA-4 checkpoint blockade therapy. Tell us how you got into that.
Dr. Allison: I began studying the basic science at the University of California at Berkley. We were interested in understanding regulation of T cell responses and I began to suspect that, in addition to positive signals that need to be given to initiate immune responses, there are also negative signals that no one had really thought of before that might limit responses. And it occurred to me that might be one reason why it was very difficult to actively mobilize the immune system to attack cancer cells. That it isn''t enough to just try to push them into going, but you have to learn how to suspend the brakes, if you will, at least temporarily, to really realize the full potential of the immune response.

And so we found this molecule called CTLA-4 that fit those criteria and showed in mouse models that simply covering up that molecule with a monoclonal antibody could lead to rejection of many types of tumors in mice.

But the really exciting thing is that there were somewhere between 20%-25% of the patients that were alive at two years, three years, four years, and now even more. So there are a lot of people who are really getting cured by this treatment.

CRI: So those were the laboratory results. Tell us about the clinical experience with ipilimumab.
Dr. Allison: It went into a very large trial in metastatic melanoma, where the survival rate is probably 12% for two years, and much, much less for three years and four years. It was very gratifying because when the results of the phase III clinical trial were unveiled, there was an eleven month increase in the overall survival, on average, in the population.

That was the first drug in history to show a survival advantage in metastatic melanoma—the first of any kind of drug. But the really exciting thing is that there were somewhere between 20%-25% of the patients who were alive at two years, three years, four years, and now even more. So there are a lot of people who are really getting cured by this treatment. That’s a strong word to use, of course. I think we have to redefine the word ‘cure’ a little bit. I think, for practical purposes, if you''re alive and are having no trouble a decade after your treatment, then I think that''s as good as a cure.

I know a patient who was treated at UCLA in the phase I trial almost 12 years ago, who said that when she was first told about ipilimumab she had failed every other drug and was hoping to hang on long enough to see her two sons graduate from high school. Well, I saw her just last week and she told me that they''ve both now finished graduate school. She’s almost 12 years out, no sign of disease, no re-treatment necessary. I think this is what we can begin to think is a reality now for immunotherapies.

CRI: How quickly will we start to see major changes in cancer treatment?
Dr. Allison: I see the field as a whole beginning to progress very rapidly from now. We know that the basic concept of checkpoint blockade works in a fraction of people. We''ve done a lot of preclinical work in mouse models showing that it works much better when you can combine it with other things, like vaccines. The nice thing about these approaches in general is that you can use the same drug for all kinds of cancer. CTLA-4 blockade has mostly been used in melanoma, but also has been shown to be effective in prostate cancer, ovarian cancer, renal cancer, and a few other types. It should be almost universally applicable to tumors, provided that we can get an immune response initiated to them. My colleague Jedd Wolchok says that’s because you''re treating the patient, not the cancer.

CRI: What do you see as the future of immunotherapy?
Dr. Allison: The way the field of immunotherapy is going now is toward combinatorial therapies, where we combine these different immune checkpoints blockers, and also combine these with drugs that actually kill tumor cells. We’ve seen long-term survivals in about a quarter of melanoma patients, but I think it’s within our easy reach of doubling that or better just in the next few years with the tools that we now have. And since we''re coming up with new tools all the time, I think it’s just a really exciting period. The preclinical and clinical studies are just exploding with new ideas.

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"CRI helps foster advances in the field that will lead to even more ways to treat cancer down the line."

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CRI: How does CRI advance the science of cancer immunotherapy?
Dr. Allison: I think CRI plays a very important role in, among other things, funding the training of young scientists and trying to interest them in cancer, particularly cancer immunology. By focusing on that particular area of funding, CRI helps foster advances in the field that will lead to even more ways to treat cancer down the line.

There’s also the CRI/Ludwig CVC Clinical Trials Network. The CVC is a network of people all over the world who share the same reagents and learn from each other and share data. I think that''s really driven the field as a model for how to proceed. And that wouldn''t have happened had there just been a lot of individual investigators going where their own nose was taking them. Now you can have these collaborations that together are much bigger than the sum of the parts.

CRI: What do you see as the major barriers to progress in the field?
Dr. Allison: One of the barriers that frustrates many of the people in the field is that the different drugs which could be used in combination are sometimes held by different companies. And it’s very difficult for reasons that have nothing to do with science, but everything to do with business to get the proper pieces to come together in a way that makes the most sense for maximum benefit. But that’s beginning to change. 

CRI: What is CRI doing to try to overcome these barriers?
Dr. Allison: CRI’s Clinical Accelerator program has started to actually engage pharmaceutical companies that have these drugs, with the goal of bridging the divide between academia and industry. CRI wants to see its scientists who have been involved in vaccine studies for many years actually have some say in how these company drugs are combined and how the trial is conducted—even perhaps suggesting a study that the company might not have thought of. I think that is going to help move the field forward much more rapidly.

It took from 1995 when we published the first paper on CTLA-4 to 2011 before it was approved, and that''s way too long. Now that we know the lessons, we know how to handle these things. So CRI can really take advantage of that knowledge to shorten the time and bring new treatments to patients much, much faster.

诺奖得主本庶佑：做研究不能死记硬背 要有好奇心和勇气

　　“被从重病中得以恢复的人说‘变得精神起来是多亏了你’的时候，真的感到研究很有意义。”

　　2018年诺贝尔生理学和医学奖被授予美国免疫学家艾利森以及日本免疫学家本庶佑，以表彰他们发现可使攻击体内异物的免疫反应停下的蛋白质，为癌症免疫疗法药物研发开辟了道路。

　　在昨天的新闻发布会上，诺奖委员会成员透露，当76岁的本庶佑在电话那头得知自己获奖时表现得很平静，甚至还有些害羞。

　　本庶佑在日本国内的记者会上称：“感到非常光荣。向长期支持我的家人以及多到数不尽的人们表示感谢。”他还就成为获奖理由的研究成果表示：“被从重病中得以恢复的人说‘变得精神起来是多亏了你’的时候，真的感到研究很有意义。”

　　有趣的是，在获奖消息刚发出时，日本国内还对本庶佑佑的姓氏起了些争议，他究竟是姓“本庶”，还是姓“本”？据日本媒体报道，“本庶”一姓在日本颇为罕见，目前仅有30人姓该姓氏。

　　本庶佑的研究团队于1992年发现作用于攻击异物的免疫细胞表面的蛋白质“PD-1”。之后还弄清了该蛋白质是防止体内免疫细胞失控的“刹车”。

　　癌细胞会擅自利用这一刹车，阻止免疫细胞对自己的攻击。如果人为地让刹车失灵，就有可能消灭癌细胞。根据该原理，本庶等人与大阪市的小野药品工业公司研发的“OPDIVO”被称为免疫哨卡抑制剂，于2014年以皮肤癌为对象上市，适用范围现已扩大至肺、肾、胃等部位的癌症。

　　“我希望我的研究能够再进一步，这样免疫疗法在未来就能够更好的帮助癌症病人们，”本庶佑在昨天的新闻发布会上表示。

　　本庶佑出生于日本京都府京都市。小时候，在阅读了日本知名细菌学家野口英世（1876-1928）的传记后，他就立下了要成为科学家的志向。1975年，他在京都大学医学部获得医学博士学位，现任美国国家科学院外籍院士，日本学士院会员。

　　2016年，本庶佑获得了国际科学大奖京都奖基础科学奖项。他在领奖时说：“做研究不仅仅要埋头苦读。阅读和记住那些论文是不会造就一个好的研究者的。要通过好奇心来自我驱动，且要有勇气面对挑战。在我看来，这才是科学的起点。”

　　日本首相安倍晋三当晚向他致电表达祝福称：“您的研究成果给众多癌症患者带来希望与光明。”

　本庶佑凭此成为日本第26位诺贝尔奖得主。事实上，从1901年至2018年的诺贝尔奖颁发历史中，日本是欧美之外获奖最多的国家，达27人，共包括物理学奖11人、化学奖7人、生理学或医学奖5人、文学奖3人、和平奖1人。进入21世纪后，日本人的获奖次数仅次于美国，居世界第二。

　　持续的国家投入、科研环境、国民教育、民族性格种种因素将日本的科学提升到了国际顶尖水平。

　　早在1995年，日本国会就通过了《科学技术基本法》，其后制定了多个5年计划。从2005年到2015年，日本这十年的科研经费平均达到国内生产总值的3%，居发达国家首位，而2016年美国为2.8%，约4650亿美元。

　　2001年3月，在第二基本计划里，日本明确提出“50年拿30个诺贝尔奖”的目标。进入21世纪到本年度，已有18位日本人获诺奖，距当年的计划已实现大半。”

　　凭借着举国在基础科学的重视和不断投入，日本人已经在半导体芯片、光学、超级计算机、超高精度机床、工业机器人、顶尖精密仪器、全球碳纤维、全球工程器械、发电用燃气机轮等领域掌握着核心力量。

癌症每年夺去数百万人的生命，是人类最大的健康挑战之一。人类在攻克癌症的路上，尝试了直接手术切除、化疗、放疗等手段，但始终没有看到彻底治愈的希望。

“通过刺激患者自身的免疫系统攻击肿瘤细胞的能力”，这是2018年的两位诺贝尔生理学或医学奖得主，70岁美国免疫学家詹姆斯·艾利森（James Allison）与76岁的日本生物学家本庶佑（Tasuku Honjo）在上世纪末、本世纪初为癌症治疗建立的一个全新的原则。而100多年以来，科学家们一直希望能够通过改进患者自身的机体免疫系统来抵御癌症。

James Allison

20世纪90年代，艾利森在加利福尼亚大学的实验室对已知蛋白——细胞毒性T细胞相关蛋白-4（Cytotoxic T lymphocyte associate protein-4，简称CTLA-4）进行了深入研究。艾利森发现，CTLA-4可以起到抑制免疫系统的作用，相当于患者免疫系统的“刹车器”。 抑制CTLA-4分子，则能使T细胞大量增殖、攻击肿瘤细胞。他意识到，如果解除这种抑制，患者的免疫细胞可以再次获得攻击肿瘤的防御能力。

Tasuku Honjo

与此同时，本庶佑在淋巴细胞膜上发现了一种免疫球蛋白受体，当时认为与细胞程序性死亡有关，故命名为PD-1（Programmed cell Death 1）。仔细研究它的功能后，最终揭示该蛋白也是作为一个“刹车器”，但作用机制不同。

艾利森和本庶佑多年的研究展示了如何解除患者自身免疫系统的“刹车器”来治疗癌症。在他们两人取得重大发现之前，癌症临床研究陷入了瓶颈，他们的开创性发现被认为是人类抗击癌症的斗争中的一个重大里程碑，并为彻底治愈癌症带来了曙光。

2011年，美国FDA批准了首个靶向CTLA-4的单克隆抗体药物（Ipilimumab）上市，用于治疗晚期黑色素瘤，这是肿瘤免疫疗法临床的“开端”。2013年，顶级学术杂志《科学》将肿瘤免疫疗法选为当年十大科学突破之首，正式确立了免疫疗法的“潜力”。 2016年、2017年，肿瘤免疫治疗两度被美国临床肿瘤学会评选为年度首要进展。

目前在免疫疗法领域被证明有效的癌种包括黑色素瘤、前列腺癌、肺癌、头颈癌、经典型霍奇金淋巴瘤、宫颈癌等。

人类自身免疫防御能对抗癌症吗

癌症类型五花八门，但各种癌症的共同特征是异常细胞不受控制地扩散，并且扩散到健康器官和组织当中。目前治疗癌症的方法包括直接手术切除、化疗、放疗等手段，该领域的一些突出贡献此前已摘得过诺奖桂冠。

例如，1966年，美国Charles Huggins医生因用激素疗法（雄激素阻断疗法）治疗前列腺癌获奖；1988年，Elion和Hitchins因化学疗法获奖；1990年，Thomas用骨髓移植疗法治疗白血病获奖。然而，进行性癌症往往仍难以治疗，研究人员迫切需要开发出新型的癌症疗法。

19世纪晚期、20世纪初期，一种新型的癌症治疗理论开始流行，即通过激活机体免疫系统或许能作为攻击肿瘤细胞的新型疗法。通俗来说，即激活调动起患者自身的天然免疫系统，从此前对癌细胞的“麻木放纵”转变为“清醒攻击”。

当时有研究人员试图利用细菌感染患者来激活机体的免疫防御机制，但收效甚微。

科学家们意识到还需要进一步深入研究。很多研究人员参与到该领域，开展了密集的基础研究，同时他们也试图研究阐明调节机体免疫力的新型机制，以及机体免疫系统如何有效识别肿瘤细胞。

尽管研究人员取得了一定的进展，但是尝试开发革命性的抗癌疗法依然困难重重。

免疫系统的加速器和刹车器

人类机体免疫系统的基本属性是能够有效区分“自我”与“非自我”。 因此，在正常情况下，机体免疫系统往往能够自动攻击和清除外来入侵的细菌、病毒和其它威胁。

以免疫系统的主力军T细胞举例，一般情况下，这些T细胞在血液里循环的时候就会起到一个“哨兵”的作用，遇到正常细胞就会把它归为“自我良民”。但人体一旦进入逐渐衰老阶段，或整体免疫力下降的时候，“哨兵”的作用会减弱。“T细胞种类也会越来越少，也就是能识别不同‘非自我’的花样变少了，就会造成识别失败。这样癌症细胞就能潜伏下来，一段时间后它的表面就会放出一些其他蛋白，并“迷惑”T细胞。

T细胞表面拥有特殊的受体，能结合一些“非自我”入侵物的结构，正是这样的结合能够触发机体免疫系统参与到防御过程中去。不过，仅仅这样还不够，往往还需要额外的蛋白质来充当T细胞“加速器”，因此免疫反应才得以完全成熟。