生物与医学2016nature.com
通过将 RNA 递送至树突状细胞进行癌症治疗
Cancer therapy by RNA delivery to dendritic cells
进阶 · 约 60 分钟读完前置知识：免疫学基础、树突状细胞与抗原呈递、mRNA 药物基础
导读
这篇 Nature 论文研究一种基于 RNA 的癌症免疫疗法：将编码肿瘤抗原的 RNA 与带正电的脂质结合，递送到树突状细胞，使其表达肿瘤抗原并激活 T 细胞的特异性免疫反应。作者称这类 RNA-LPX 疫苗生产快速、成本低廉，几乎可编码任意肿瘤抗原，有望实现个性化的癌症“疫苗”治疗。
HN 关注点：这种 mRNA 递送抗癌疫苗思路（BioNTech 的工作）被视为可低成本推广到多种癌症的平台技术，HN 读者关注其机制、适用范围和落地前景。
HN 评论精选
这几条评论里：支持 1 补充 2 亲历 1
支持详细解释了树突状细胞递送 RNA 激活免疫的原理及脂质载体设计
这是一个理论上很有前景的方法，如果成功，可以较容易地为每个患者的癌症开发个性化的“疫苗”。背景：树突状细胞是抗原呈递细胞，负责把蛋白质分解成小片段（抗原）展示给 T 细胞，T 细胞据此判断是自身抗原还是外来抗原并决定是否发起免疫攻击。基本思路是让树突状细胞生产目标蛋白并展示出来——把编码该蛋白的 RNA 喂给树突状细胞即可。额外的好处是，游离 RNA 会触发抗病毒防御，使 T 细胞对所检查的抗原更加“警惕”，降低发起免疫反应的阈值。但直接往脾脏注射 RNA 不现实，所以他们发现把带负电的 RNA 按特定比例附着到带正电的脂质上（形成特定的电荷/质量比），能让其定位到脾……
rcthompson查看英文原文
This is certainly an interesting and theoretically promising method, that, if it works, should make it fairly easy to develop specific personalized "vaccines" for each person's cancer. For background, dendritic cells are a type of antigen-presenting cells, which means their job is to pick up proteins, break them up into small pieces (antigens), and then show those pieces to T-cells, whereupon the T-cells can either say "looks like a self antigen, everything's fine" or say "that looks like a foreign antigen, raise the alarm!" and then initiate a specific immune response against that antigen. The basic concept here is that if you have a specific protein that you want to raise an immune response against, you can do so by tricking dendritic cells into producing copies of that protein, which will then get presented along with all the other antigens for inspection by T-cells. You can pull off this trick by feeding RNA that encodes the target protein to the dendritic cells, and as a bonus, the fact that there's free RNA floating around triggers anti-viral defenses, which causes the T-cells to be extra suspicious of the antigens they're inspecting (i.e. it lowers their threshold for raising an immune response). But injecting RNA directly into your spleen isn't exactly practical, so instead they found that attaching the negatively charged RNA to some positively charged lipids in a specific ratio (which results in a specific ratio of charge to mass) causes them to localize to the spleen and then get taken up, translated, and presented by dendritic cells when injected intravenously. So, put it all together, and the workflow for treating cancer looks something like this: 1. Find a protein produced by the cancer cells that is either sufficiently different from the same protein in normal cells (due to mutation) or not produced in normal cells. 2. Construct an RNA transcript that will produce that protein when translated. 3. Attach that RNA transcript to the liposomes in the appropriate ratio, and inject it into your bloodstream. 4. Let the immune system do its thing. 5. Repeat as necessary to keep the immune response active until it's killed all the cancer. Obviously step 1 is still the hard part, and the paper chose as a proof of concept two example cancers for which this step was already done. But finding a viable cancer-specific antigen is certainly orders of magnitude easier than determining the mechanism of a cancer and then developing a treatment specific to that mechanism.
亲历从患者家属视角表达期待，同时担忧临床试验周期漫长
（付费墙）我理解这是一种类似疫苗的免疫疗法。很想知道对哪些癌症效果最强，文中列出的是肺部软组织肿瘤。下面的引文表明它可能对所有癌症类型有效且成本低廉，令人兴奋。但要等到儿童试验恐怕还要 5 年？（我的儿子和妹妹死于癌症，我女儿 10 岁的朋友正参加免疫疗法试验，我们祈祷奇迹降临她的复发性脑癌。）引文：RNA-LPX 疫苗生产快速廉价，几乎任何肿瘤抗原都可用 RNA 编码。
baldfat查看英文原文
Paywall: I read this as an ability to help in immunotherapy which works like a vaccine. I really am interested in what types of cancer this works with the strongest effect. They list soft tumors in Lungs. The bellow citation seems to show that these are something that could work on all cancer types and is cheap. These are exciting times. Now it will be another 5 years till we see this even in a trial for children? (Son and sister died of cancer and my daughter's 10 year old friend (same cancer as my sister) is in immunotherapy trial which we are praying for a miracle for her reoccurring brain cancer. > RNA-LPX vaccines are fast and inexpensive to produce, and virtually any tumour antigen can be encoded by RNA.
补充指出媒体关注随机，强调平台低成本适配才是癌症疗法普及的关键
论文链接和公司（BioNTech）新闻稿。说实话，哪些癌症研究能获得媒体和公众关注相当随机，与优劣关系不大。应假设任何一篇这样的文章背后都有许多类似研究默默无闻地被忽略。对于立志在下一代癌症研究中广泛应用的方法，最重要的是将其适配到特定癌症的成本有多低——真正控制癌症的唯一途径是压低针对不同癌症的应对成本，让每次适配只是小项目而非全新的研究计划。
reasonattlm查看英文原文
Paper: http://dx.doi.org/10.1038/nature18300 Company release: http://biontech.de/2016/06/01/nature-publication-describes-first-example-of-a-clinically-applicable-and-systemic-mrna-cancer-immunotherapy-vaccine/ Really it is pretty random as to what cancer research and development gets more or less attention from the media and public. Merit has little to do with it. You should assume that any given article like this is representative of many similar ones that passed by without comment. The most important thing for any approach aspiring to be widespread in the next generation of cancer research is how costly it is to adapt the platform to any specific cancer. The only way to make real inroads in control of cancer is to crush down the cost of addressing different cancers, making it a small project rather than a whole new research initiative each time around.
补充分享了论文全文的免费阅读链接
给感兴趣的人提供全文链接：http://rdcu.be/iFZr
superfx查看英文原文
Here's the full article for those interested: http://rdcu.be/iFZr
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