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肿瘤免疫疗法:多突变癌症克星—抗癌管家互助群
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发表时间:2018-12-07 09:19作者:抗癌管家

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她已经和肺癌搏斗了11年;他是曾经的肝癌患者...7年来,他们在群里为大家传授抗癌经验......“抗癌管家互助群”,是大家共同的抗癌家园。

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群里有来自北京胸科医院、北京协和医院、上海瑞金医院等名医指导抗癌。还有十几年抗癌经验的抗癌明星一起分享。

祝愿每个患者和家属都健康平安。抗癌管家-你身边的抗癌专家。


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图片:人类结肠癌细胞,来源:URBAIN WEYEMI, CHRISTOPHE E. REDON, WILLIAM M. BONNER


译文来自:生物谷

原出处来自:环球科学

作者:Jocelyn Kaiser

翻译 谢梦莹

审稿 董子晨曦



临床试验中使用的新型免疫系统激活抗癌药物让许多看似无法治愈的黑素瘤或肺癌患者重获新生,但这些药物对结肠癌似乎无效。不过有一个例外——一位男性患者的结肠癌转移瘤在2007年接受药物治疗后消失了——引起了研究人员的兴趣。他们怀疑该患者之所以能够康复,可能与肿瘤中出现大量突变有关。如今,一个小型临床试验表明,即使是新药一般不起作用的某些类型的肿瘤,如果恰好出现了大量的突变,就也能用这类药物治疗,患有这些肿瘤的患者中有3%~4%会从中受益。


上述实验测试的药物是一种抗体,可以阻断免疫系统T细胞表面的PD-1受体。肿瘤细胞通过激活PD-1受体逃避T细胞攻击。但是,当PD-1抑制剂阻断了这个免疫系统的“检查站”,T细胞就能识别并攻击肿瘤细胞。这种药物和另外一种利用免疫系统的新癌症疗法让人们欢欣鼓舞,因为对于某些晚期癌症患者,这些疗法能长期抑制肿瘤。黑色素瘤和肺癌对PD-1抑制剂的反应最好,对此的猜想是,这两种癌症与其它癌症相比会产生更多突变。其中一些突变会改变基因,从而编码可被免疫系统识别为异物的异常蛋白(抗原)。突变越多,这种肿瘤抗原也就越多,肿瘤抗原可以刺激被PD-1抑制剂释放的T细胞产生攻击行为。


美国约翰·霍普金斯大学的研究人员们检测了第一个对PD-1抑制剂产生应答的结肠癌男性患者的肿瘤组织,发现了这样一个线索:他的肿瘤组织中“错配修复”的基因存在突变,这些基因编码的蛋白质的功能是在细胞基因复制时修复DNA碱基错误。如果这些基因不能正常表达,就有可能让致癌的基因突变出现,并最终导致结肠癌,肿瘤中将含至少1000处突变,是一般组织的10至100倍。霍普金斯大学研究团队想知道,患有其他各种癌症的患者,如果肿瘤中的错配修复基因存在突变,是否也对PD-1抑制剂产生应答。


为了探究这一想法,霍普金斯大学的肿瘤学家Dung Le,Luis Diaz及其他人寻找了取自晚期癌症患者的肿瘤样本中的,其他疗法对这些患者已经无效。按照患者是否含有错配修复基因突变,研究人员将48名患者分为2组。每隔2周给所有患者使用PD-1抑制剂pembrolizumab (Keytruda)。


上述2组试验的结果大相径庭。有错配修复基因突变的个体更易产生应答——在13名结肠癌患者中,8名患者的肿瘤组织缩小,4名患者保持稳定,只有1人病情恶化。与之相反的是,在25名没有错配修复基因突变的结肠癌患者中,没有1名患者对药物产生应答。一些产生应答的患者还可存活1年或更长时间,而未产生应答的患者平均寿命为7.6个月。在患有其他类型肿瘤(包括胰腺癌、前列腺癌、子宫癌)的10名含有错配修复基因突变的患者中,7名患者病情好转或稳定,另外3名患者病情有所发展。该研究刊登在《新英格兰医学杂志》(The New England Journal of Medicine)上。Le在最近举办的美国临床肿瘤协会年会上介绍了最新结果。


Diaz称,结果显示,带有错配修复基因缺陷的癌症患者占所有癌症患者的3%~4%(PD-1抑制剂有效人群)。“这只是一小部分,并不适于全部癌症。”他说,但仍然可以使美国3万至4万晚期癌症患者延长1年寿命。


此研究也支持另一说法,肿瘤中的基因突变越多——不论是由于错配修复基因的问题,还是其它原因——PD-1抑制剂或类似药物就越可能对其有效,纪念斯隆-凯特琳癌症中心(Memorial Sloan-Kettering Cancer Center)的癌症免疫疗法研究者Jedd Wolchok说。他的团队最近报道,编码新肿瘤抗原的突变越多,黑素瘤和肺癌患者就越易对免疫“检查站”的阻断剂产生应答。霍普金斯大学的研究“给了我们很大信心,让我们相信,我们之前的发现是十分重要的”,他说。该发现的一个推论是,肿瘤中基因突变较少的癌症患者如果先接受放射治疗或化学治疗,那么对PD-1抑制剂的应答会变得更好,因为放疗和化疗会使肿瘤产生新的突变。尽管一些患者在PD-1抑制剂临床试验中已经尝试了这一方法,但仍没有研究者设计专门的临床试验研究该问题,“因此很难就此得出结论”,Diaz说。


以下是原文:


Cancer immunotherapy takes aim at mutation-riddled tumors


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Jocelyn is a staff writer for Science magazine.


By Jocelyn Kaiser 29 May 2015 2:30 pm 1 Comment

New immune system-boosting cancer drugs have in clinical trials saved the lives of many people with seemingly untreatable melanoma or lung cancer, but the drugs seem useless against colon cancer. One exception—a man with colon cancer whose metastatic tumors vanished for several years after he was treated in 2007—piqued researchers' interest. They suspected his recovery might have to do with the large number of mutations in his tumors. Now, a small clinical trial suggests that even cancer patients with types of tumors that were thought to be impervious to the new drugs could benefit if those malignancies have the right error-riddled DNA signature, a result that could help 3% to 4% of cancer patients.


The drug tested is an antibody that blocks a receptor called PD-1 on the surface of the immune system’s T cells. Tumor cells can hide from T cells by activating the PD-1 receptor; when this immune “checkpoint” is blocked by a PD-1 inhibitor, however, the T cells see the tumor cells and can attack them. Such drugs are among two new types of immune system–harnessing cancer treatments that have generated tremendous excitement, because in some patients with advanced cancer, they keep tumors at bay for years. One hypothesis about why melanoma and lung cancer respond best to PD-1 inhibitors is that these two cancer types tend to have more mutations than other cancers. Some of these mutations may alter genes so that they code for small stretches of abnormal proteins that the immune system sees as foreign proteins, or antigens. The more mutations, the more of these “neoantigens” that can trigger an attack from T cells that have been unleashed by a PD-1 inhibitor.


When researchers at Johns Hopkins University in Baltimore, Maryland, examined tumor tissue from the original man with colon cancer who responded to a PD-1 inhibitor, they found a clue: His tumor had mutations in “mismatch repair” genes, so-called because their encoded proteins fix errors in DNA bases when cells replicate their DNA. When these genes don’t work properly, they can lead to cancer-promoting mutations and result in a colon tumor riddled with 1000 or more mutations, 10 to 100 times the usual number. The Hopkins group wondered if patients with many cancer types who had tumors with errors in mismatch repair genes would respond to PD-1 inhibitors.


To explore this idea, Hopkins oncologists Dung Le, Luis Diaz, and others looked for mismatch repair mutations in tumor samples from patients with advanced colon cancer and other cancer types whose tumors had stopped responding to other treatments. They divided 48 patients into two groups, those with and without these mutations in their tumors. Then they gave all of them a PD-1 inhibitor called pembrolizumab (Keytruda) every 2 weeks.


The difference in the results was dramatic. Those with mismatch repair mutations were far more likely to respond—of 13 with colorectal cancer, eight saw their tumors shrink, four remained stable, and only one got worse. By contrast, not a single one of 25 colorectal patients lacking mutations in mismatch repair genes responded. Some of the patients who responded are still alive after a year or more, whereas the nonresponders lived on average only 7.6 months. Of 10 patients with other types of cancer—including pancreatic, prostate, and uterine—who had mismatch repair mutations, in seven their tumors shrank or remained stable; the other three progressed. The study will appear tomorrow in The New England Journal of Medicine, and Le will present updated results at the annual meeting of the American Society of Clinical Oncology in Chicago tomorrow.


The results suggest that the 3% to 4% of all cancer patients with mismatch repair defects in their tumors could benefit from PD-1 inhibitors, Diaz says. “It’s a slice. It’s not all cancer,” he says. Still, that could add up to 30,000 to 40,000 advanced cancer patients a year in the United States, he says.


The study also supports the idea that tumors with more mutations—whether from mismatch repair defects or for other reasons—are more likely to respond to PD-1 inhibitors and similar drugs, says immunotherapy cancer researcher Jedd Wolchok of the Memorial Sloan Kettering Cancer Center in New York City. His team has recently reported that melanoma and lung cancer patients with more neoantigen-coding tumor mutations are more likely to respond to immune checkpoint blockers. The Hopkins study “gives us very good confidence that what we’ve seen before is important,” he says. One implication is cancer patients with few mutations in their tumors might respond better to PD-1 inhibitors if they first receive radiation or chemotherapy, because these treatments can create new mutations in tumors. Although some patients in PD-1 inhibitor trials have had such prior treatments, without a trial designed to address the question, “it’s hard to draw conclusions,” Diaz says.


Posted in Biology, Health


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她已经和肺癌搏斗了11年;他是曾经的肝癌患者...7年来,他们在群里为大家传授抗癌经验......“抗癌管家互助群”,是大家共同的抗癌家园。

欢迎大家添加抗癌管家微信920 670 720,加入抗癌管家互助群和大家多交流。

群里有来自北京胸科医院、北京协和医院、上海瑞金医院等名医指导抗癌。还有十几年抗癌经验的抗癌明星一起分享。

祝愿每个患者和家属都健康平安。抗癌管家-你身边的抗癌专家。

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