研究发现，免疫疗法可能无法帮助某些肝癌患者

StephenW

Immunotherapy may not help certain liver cancer patients, study finds

Advanced liver cancer is notoriously difficult to treat. New findings suggest it's even harder than we knew..
    Marie McCullough
    by Marie McCullough
    Published Apr 7, 2021

Until recently, the standard treatment for patients newly diagnosed with advanced liver cancer was a drug that blocks certain cell molecules. Unfortunately, Sorafenib has rough side effects and usually doesn’t work; only about 11% of late-stage patients survive five years.

Immune-boosting drugs called checkpoint inhibitors are improving that grim outlook. A year ago, results of a ground-breaking clinical trial led to the first approval in a dozen years of a new initial treatment regimen that includes Tecentriq, a checkpoint inhibitor.

But now, research by an international group suggests that the effectiveness of this pricey class of drugs depends on the roots of the liver malignancy — whether it is linked to a viral infection, alcohol abuse, or a severe form of non-alcoholic fatty liver disease.

The research, published last month in Nature, began with studies in animal models and human liver samples. That prompted a re-analysis of three clinical trials of checkpoint inhibitors.


The conclusion: Liver cancer patients with a history of hepatitis B or C infections had tumor shrinkage and extended survival with immunotherapy. The rest of the patients did not benefit, although the researchers could not distinguish cancers related to alcohol damage from cancers related to severe fatty liver disease.

Senior author Josep M. Llovet, who directs the liver cancer program at Mount Sinai Hospital’s Tisch Cancer Institute, said the implications are huge for several reasons.

At least five clinical trials are underway worldwide aimed at further expanding the role of checkpoint inhibitors in liver cancer treatment. Meanwhile, severe fatty liver disease is becoming more common because it is linked to a modern lifestyle affliction: obesity.

“Now, we have a new challenge,” Llovet said in an interview. “How are we going to distinguish and treat liver cancer patients” with a history of severe fatty liver disease?

Fox Chase Cancer Center oncologist Jason A. Castellanos, who specializes in liver cancer, agreed.

“We thought we had an [immunotherapy] breakthrough last year, but now we know we need to see if there are differences” related to the cause of the cancer, he said. “This will probably redefine how liver cancer clinical trials ask questions in the future.”

Currently, there is no simple blood or urine test that can classify liver cancer patients based on viral or non-viral causes.

What’s more, most people with excessive fat in their livers go undiagnosed because the condition usually has no symptoms — not even when it progresses to the severe form, called nonalcoholic steatohepatitis, which is marked by inflammation, scarring and liver cell injury. Diagnosis requires imaging or a biopsy, or both.
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It is not clear why some liver damage progresses to cancer.

“However, more than half of all people diagnosed have cirrhosis, a scarring condition of the liver commonly caused by chronic alcohol abuse and viral hepatitis,” wrote Sapna Parmar, an oncology pharmacist at Oncology Analytics.

This year, an estimated 42,000 people will be diagnosed with liver cancer, in most cases linked to viral hepatitis.

But studies are tracking a shift. Hepatitis is now readily curable in mere months with powerful new drugs, so cancer can be averted. Fatty liver disease, meanwhile, affects up to 40% of U.S. adults, or 83 million people — and counting. More than a million of them will progress to steatohepatitis, and as many as 33,000 of those will ultimately be diagnosed with liver cancer.
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Checkpoint inhibitors have transformed the outlook for numerous solid-tumor cancers. (Think of former President Jimmy Carter, who was cured by Keytruda after melanoma spread to the nonagenarian’s brain and liver in 2015.)

These revolutionary drugs work by removing a molecular brake, or “checkpoint,” that cancer exploits to evade T cells, the disease-fighting soldiers of the immune system.

Llovet’s team of 110 scientists discovered nuances. While a checkpoint inhibitor dramatically shrank tumors in a mouse model of viral-induced liver cancer, the drug actually promoted tumor growth in a mouse model of cancer that started with severe fatty liver disease.

“This was shocking and very provocative,” Llovet said. “So then we went to humans, to the three existing trials of checkpoint inhibitors.”

Their analysis found clear benefits for the 900 patients with viral-related cancers, but not for the 700 with non-viral origins.

The researchers acknowledged that their findings are limited because the three trials had varying treatment combinations and designs, and did not distinguish between cancers linked to alcohol vs.  fatty liver disease.

StephenW

研究发现，免疫疗法可能无法帮助某些肝癌患者

众所周知，晚期肝癌很难治疗。新发现表明，这比我们所知道的还要困难。
    玛丽·麦卡洛（Marie McCullough）
    玛丽·麦卡洛（Marie McCullough）
    2021年4月7日发布

直到最近，针对新诊断为晚期肝癌的患者的标准治疗方法是阻断某些细胞分子的药物。不幸的是，索拉非尼的副作用很严重，通常不起作用；只有约11％的晚期患者可以存活5年。

称为检查点抑制剂的增强免疫力的药物正在改善这种严峻的前景。一年前，一项开创性的临床试验结果导致十几年来首次批准了包括检查点抑制剂Tecentriq在内的新的初始治疗方案。

但是现在，一个国际组织的研究表明，这类昂贵药物的有效性取决于肝脏恶性肿瘤的根源-是否与病毒感染，酗酒或严重的非酒精性脂肪肝疾病有关。

这项研究于上个月在《自然》杂志上发表，开始于对动物模型和人类肝脏样本的研究。这促使对三项检查点抑制剂的临床试验进行重新分析。


结论：有乙型或丙型肝炎感染史的肝癌患者肿瘤缩小，并通过免疫疗法延长了生存期。尽管研究人员无法将与酒精损害相关的癌症与与严重脂肪肝相关的癌症区分开来，但其余患者并未受益。

在西奈山医院Tisch癌症研究所负责肝癌研究的资深作者Josep M. Llovet说，这种影响之所以巨大，有几个原因。

全世界正在进行至少五项临床试验，旨在进一步扩大检查点抑制剂在肝癌治疗中的作用。同时，严重的脂肪肝疾病正变得越来越普遍，因为它与现代生活方式造成的肥胖有关：肥胖。

洛洛夫在接受采访时说：“现在，我们面临着新的挑战。”有严重脂肪肝病史的“我们如何区分和治疗肝癌患者”？

Fox Chase癌症中心的肿瘤学家Jason A. Castellanos专门研究肝癌，对此表示同意。

他说：“我们以为去年我们在[免疫疗法]方面取得了突破，但是现在我们知道我们需要看看是否存在与癌症原因有关的差异。” “这可能会重新定义未来肝癌临床试验如何提出问题。”

当前，没有简单的血液或尿液检查可以根据病毒或非病毒原因对肝癌患者进行分类。

而且，大多数肝脏脂肪过多的人都无法诊断，因为这种病通常没有症状-即使病情发展到称为非酒精性脂肪性肝炎的严重形式，也没有出现，其特征是炎症，瘢痕形成和肝细胞损伤。诊断需要影像学检查或活检，或两者同时进行。
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目前尚不清楚为什么某些肝脏损害会发展为癌症。

“但是，被诊断出的所有人中有超过一半患有肝硬化，这通常是由慢性酒精滥用和病毒性肝炎引起的肝脏瘢痕形成，” Oncology Analytics的肿瘤药师Sapna Parmar写道。

今年，估计将有42,000人被诊断出患有肝癌，大多数情况下与病毒性肝炎有关。

但是研究正在跟踪变化。现在，只要使用强大的新药就可以在短短几个月内治愈肝炎，因此可以避免癌症。同时，脂肪肝疾病影响着多达40％的美国成年人，即8300万人，而且这一数字还在不断增加。其中超过一百万将发展为脂肪性肝炎，其中多达33,000最终将被诊断出患有肝癌。
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检查点抑制剂已改变了许多实体瘤癌症的前景。 （想想前总统吉米·卡特（Jimmy Carter），他在2015年黑素瘤扩散到这位普通科医生的大脑和肝脏后被Keytruda治愈了。）

这些革命性的药物通过消除分子制动器或“检查点”来起作用，癌症利用该分子制动器逃避了免疫系统中抗击疾病的T细胞。

洛洛夫（Llovet）的110位科学家小组发现了细微差别。尽管检查点抑制剂可以在病毒诱发的肝癌的小鼠模型中显着缩小肿瘤的范围，但该药物实际上可以在以严重脂肪肝病开始的癌症小鼠模型中促进肿瘤的生长。

洛洛夫说：“这令人震惊，而且极具挑衅性。” “因此，我们开始研究人类，以及现有的三个检查点抑制剂试验。”

他们的分析发现，对于900例与病毒相关的癌症患者而言，明显的益处，但对于700例非病毒来源的患者却没有。

研究人员承认，他们的发现是有限的，因为这三项试验具有不同的治疗组合和设计，并且没有区分与酒精与脂肪肝相关的癌症。

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学习了，谢谢你的文章。