This kids’ brain cancer is incurable — but immune therapy holds promise
这个孩子的脑癌是无法治愈的，但免疫疗法是有希望的This kids’ brain cancer is incurable — but immune therapy holds promise這個孩子的腦癌是無法治癒的——但是免疫療法有希望

Every two weeks at Seattle Children’s Hospital in Washington, a five-year-old child stops by for a fresh dose of genetically engineered immune cells administered directly into the fluid around their brain.
在华盛顿的西雅图儿童医院，每两周就会有一名五岁的孩子停下来接受新鲜剂量的基因工程免疫细胞，直接注射到他们大脑周围的液体中。Every two weeks at Seattle Children’s Hospital in Washington, a five-year-old child stops by for a fresh dose of genetically engineered immune cells administered directly into the fluid around their brain.

The child has been making these visits for more than three years, after they were diagnosed with a devastating form of brain and spinal cancer called diffuse midline glioma that has no known cure. But the treatment, called CAR-T-cell therapy, appears to have shrunk their tumour and kept it in check. At 70 treatments and counting, this five-year-old might have received more doses of CAR-T-cell therapy than anyone else on the planet.
在他们被诊断出患有一种毁灭性的脑癌和脊柱癌后，这个孩子已经进行了三年多的访问，称为弥漫性中线神经胶质瘤，目前尚无治愈方法。但这种名为CAR-T细胞疗法的治疗方法似乎已经缩小了他们的肿瘤并控制住了它。在70次治疗中，这个五岁的孩子可能比地球上任何其他人都接受了更多的CAR-T细胞治疗剂量。The child has been making these visits for more than three years, after they were diagnosed with a devastating form of brain and spinal cancer called diffuse midline glioma that has no known cure. But the treatment, called CAR-T-cell therapy, appears to have shrunk their tumour and kept it in check. At 70 treatments and counting, this five-year-old might have received more doses of CAR-T-cell therapy than anyone else on the planet.

His oncologist, Nicholas Vitanza, lights up whenever he talks about the results. Still, Vitanza is keenly aware that the child's response is unusual. Although several children in Vitanza’s clinical trial might also have benefited from the CAR-T-cell regimen, most responses were not as dramatic or long-lasting as the five-year-old’s. Now, the question that keeps Vitanza and others in his field up at night is: how can they make that success less of an outlier?
他的肿瘤学家尼古拉斯·维坦萨（Nicholas Vitanza）每当谈到结果时都会亮起灯。尽管如此，维坦扎还是敏锐地意识到孩子的反应是不寻常的。尽管Vitanza临床试验中的几名儿童也可能从CAR-T细胞方案中受益，但大多数反应并不像五岁的孩子那样剧烈或持久。现在，让 Vitanza 和他所在领域的其他人夜不能寐的问题是：他们如何才能让这种成功不那么离群？His oncologist, Nicholas Vitanza, lights up whenever he talks about the results. Still, Vitanza is keenly aware that the child's response is unusual. Although several children in Vitanza’s clinical trial might also have benefited from the CAR-T-cell regimen, most responses were not as dramatic or long-lasting as the five-year-old’s. Now, the question that keeps Vitanza and others in his field up at night is: how can they make that success less of an outlier?

At the International Symposium on Pediatric Neuro-Oncology in Philadelphia, Pennsylvania, which ended earlier this month, Vitanza and other researchers presented tantalizing early clinical-trial results that suggested CAR T cells could be effective treatments for deadly central-nervous-system cancers in children.
在本月早些时候于宾夕法尼亚州费城举行的小儿神经肿瘤学国际研讨会上，Vitanza和其他研究人员展示了诱人的早期临床试验结果，表明CAR T细胞可以有效治疗致命的儿童中枢神经系统癌症。At the International Symposium on Pediatric Neuro-Oncology in Philadelphia, Pennsylvania, which ended earlier this month, Vitanza and other researchers presented tantalizing early clinical-trial results that suggested CAR T cells could be effective treatments for deadly central-nervous-system cancers in children.

The trials were designed to test the therapy’s safety rather than its effectiveness, and larger trials are needed to know for sure whether the treatments are beneficial. In the meantime, researchers are eager to find ways to tweak their approach to maximize its reach. “We’re seeing a glimpse of a signal” that the approach could work, says Jasia Mahdi, a paediatric neurologist at Texas Children’s Hospital in Houston. “Our task now is to figure out how we expand on that.”
这些试验旨在测试该疗法的安全性而不是其有效性，并且需要更大规模的试验来确定治疗是否有益。与此同时，研究人员渴望找到调整方法的方法，以最大限度地扩大其影响范围。“我们看到了一个信号”，即这种方法可能有效，休斯顿德克萨斯儿童医院的儿科神经学家Jasia Mahdi说。“我们现在的任务是弄清楚我们如何扩展它。The trials were designed to test the therapy’s safety rather than its effectiveness, and larger trials are needed to know for sure whether the treatments are beneficial. In the meantime, researchers are eager to find ways to tweak their approach to maximize its reach. “We’re seeing a glimpse of a signal” that the approach could work, says Jasia Mahdi, a paediatric neurologist at Texas Children’s Hospital in Houston. “Our task now is to figure out how we expand on that.”

Tumour-finding T cells 肿瘤发现T细胞Tumour-finding T cells

CAR-T-cell therapies consist of immune cells called T cells that have been removed from the recipient and engineered to produce molecules dubbed chimeric antigen receptors (CAR) on their surfaces. These T cells are readministered into the body, where their new receptors enable them to recognize and destroy cancer cells.
CAR-T细胞疗法由称为T细胞的免疫细胞组成，这些细胞已从受体中移除，并被设计为在其表面产生称为嵌合抗原受体（CAR）的分子。这些T细胞被重新注入体内，在那里它们的新受体使它们能够识别和破坏癌细胞。CAR-T-cell therapies consist of immune cells called T cells that have been removed from the recipient and engineered to produce molecules dubbed chimeric antigen receptors (CAR) on their surfaces. These T cells are readministered into the body, where their new receptors enable them to recognize and destroy cancer cells.

Last-resort cancer therapy holds back disease for more than a decade
最后的癌症疗法可以阻止疾病十多年Last-resort cancer therapy holds back disease for more than a decade

Despite lingering safety concerns, the approach has shown success in treating several blood cancers and, in some cases, has produced remissions lasting more than a decade. But using CAR-T-cell treatments to treat solid tumours such as those of the brain and lung is more challenging. Solid tumours can contain various cells with different mutations and differing sensitivities to the therapy. Solid tumours can also be more difficult for the T cells to penetrate.
尽管存在挥之不去的安全问题，但该方法已在治疗多种血癌方面取得了成功，在某些情况下，已经产生了持续十多年的缓解。但是，使用CAR-T细胞治疗实体瘤（如脑和肺）更具挑战性。实体瘤可以包含具有不同突变和对治疗不同敏感性的各种细胞。实体瘤也可能更难被 T 细胞穿透。Despite lingering safety concerns, the approach has shown success in treating several blood cancers and, in some cases, has produced remissions lasting more than a decade. But using CAR-T-cell treatments to treat solid tumours such as those of the brain and lung is more challenging. Solid tumours can contain various cells with different mutations and differing sensitivities to the therapy. Solid tumours can also be more difficult for the T cells to penetrate.

Even so, studies in mice have suggested that CAR T cells might work against diffuse midline gliomas. New therapies for the cancer are desperately needed: the standard treatment is radiation occasionally paired with chemotherapy, but the cancer is fatal and median survival is about 13 months after diagnosis, says Vitanza.
即便如此，对小鼠的研究表明，CAR T细胞可能对弥漫性中线胶质瘤起作用。Vitanza说，迫切需要新的癌症疗法：标准治疗方法是偶尔放疗与化疗配对，但癌症是致命的，诊断后中位生存期约为13个月。Even so, studies in mice have suggested that CAR T cells might work against diffuse midline gliomas. New therapies for the cancer are desperately needed: the standard treatment is radiation occasionally paired with chemotherapy, but the cancer is fatal and median survival is about 13 months after diagnosis, says Vitanza.

Success: a diploma 成功：文凭Success: a diploma

Now, the first CAR-T therapy clinical trials against diffuse midline gliomas in children have finished, and the results are promising. At the meeting in Philadelphia, Vitanza presented data from a trial in which 21 children with diffuse midline glioma were treated with CAR T cells that target a protein called B7-H3, which is found predominantly on cancer cells. Only one of those participants experienced a severe reaction to the treatment itself, and some have lived longer than expected, Vitanza says.
现在，针对儿童弥漫性中线胶质瘤的首个CAR-T疗法临床试验已经结束，结果令人鼓舞。在费城举行的会议上，Vitanza 展示了一项试验的数据，其中 21 名患有弥漫性中线神经胶质瘤的儿童接受了靶向一种称为 B7-H3 的蛋白质的 CAR T 细胞治疗，这种蛋白质主要存在于癌细胞上。维坦扎说，这些参与者中只有一人对治疗本身有严重的反应，有些人的寿命比预期的要长。Now, the first CAR-T therapy clinical trials against diffuse midline gliomas in children have finished, and the results are promising. At the meeting in Philadelphia, Vitanza presented data from a trial in which 21 children with diffuse midline glioma were treated with CAR T cells that target a protein called B7-H3, which is found predominantly on cancer cells. Only one of those participants experienced a severe reaction to the treatment itself, and some have lived longer than expected, Vitanza says.

Mahdi presented data from a clinical trial of a T-cell therapy that targets a molecule called GD2. In that trial, conducted at Stanford University in California, nine people with diffuse midline glioma received treatment, and tumours shrank by more than half in four of them.
Mahdi展示了一项针对GD2分子的T细胞疗法的临床试验数据。在加利福尼亚州斯坦福大学进行的这项试验中，九名弥漫性中线胶质瘤患者接受了治疗，其中四分之四的肿瘤缩小了一半以上。Mahdi presented data from a clinical trial of a T-cell therapy that targets a molecule called GD2. In that trial, conducted at Stanford University in California, nine people with diffuse midline glioma received treatment, and tumours shrank by more than half in four of them.

That trial also had an outlier: a young man whose cancer disappeared entirely and who has remained cancer-free for the more than 30 months since his first treatment. In that time, he has graduated high school and is now thriving at university. “All those normal things mean so much more in this context,” says Mahdi. “This reality wouldn’t have been his otherwise.”
该试验也有一个异常值：一名年轻人的癌症完全消失，自第一次治疗以来的30多个月里一直没有癌症。在那段时间里，他已经高中毕业，现在在大学里茁壮成长。“在这种情况下，所有这些正常的事情都意味着更多，”马赫迪说。“否则，这个现实就不会是他的了。”That trial also had an outlier: a young man whose cancer disappeared entirely and who has remained cancer-free for the more than 30 months since his first treatment. In that time, he has graduated high school and is now thriving at university. “All those normal things mean so much more in this context,” says Mahdi. “This reality wouldn’t have been his otherwise.”

A menu of choices 选择菜单A menu of choices

The researchers are eager to find ways to extend these dramatic responses to more of their study participants. Vitanza’s team has launched another trial that will test CAR T cells that target four different molecules found predominantly on brain and spinal tumours, in hopes that T cells that recognize multiple targets will be more effective.
研究人员渴望找到将这些戏剧性反应扩展到更多研究参与者的方法。Vitanza的团队已经启动了另一项试验，该试验将测试靶向主要在脑和脊柱肿瘤中发现的四种不同分子的CAR T细胞，希望识别多个靶标的T细胞将更有效。The researchers are eager to find ways to extend these dramatic responses to more of their study participants. Vitanza’s team has launched another trial that will test CAR T cells that target four different molecules found predominantly on brain and spinal tumours, in hopes that T cells that recognize multiple targets will be more effective.

Searching for the roots of brain cancer
寻找脑癌的根源Searching for the roots of brain cancer

Another team at the University of California, San Francisco, is testing CAR T cells that express the cancer-seeking receptor only when the cells are in the central nervous system. The hope is that the T cells will be active solely where they are needed, making them less likely to become dysfunctional from “exhaustion”, a phenomenon known to limit the effectiveness of T-cell therapies, says Hideho Okada, who studies immunotherapies and is a lead investigator on the project. The team treated their first clinical-trial participant — an adult with an aggressive brain cancer called glioblastoma — in June and plans to launch a similar study in children next.
加州大学旧金山分校的另一个研究小组正在测试CAR T细胞，这些细胞仅在细胞位于中枢神经系统中时才表达寻癌受体。希望T细胞将仅在需要它们的地方活跃，使它们不太可能因“疲惫”而变得功能失调，这种现象已知会限制T细胞疗法的有效性，研究免疫疗法的Hideho Okada说，他是该项目的首席研究员。该团队在6月份治疗了他们的第一位临床试验参与者 - 一名患有称为胶质母细胞瘤的侵袭性脑癌的成年人，并计划接下来在儿童中启动一项类似的研究。Another team at the University of California, San Francisco, is testing CAR T cells that express the cancer-seeking receptor only when the cells are in the central nervous system. The hope is that the T cells will be active solely where they are needed, making them less likely to become dysfunctional from “exhaustion”, a phenomenon known to limit the effectiveness of T-cell therapies, says Hideho Okada, who studies immunotherapies and is a lead investigator on the project. The team treated their first clinical-trial participant — an adult with an aggressive brain cancer called glioblastoma — in June and plans to launch a similar study in children next.

Such modifications to CAR-T-cell therapies are only the beginning, says Vitanza. Researchers are hunting for more ways to supercharge CAR-T-cell therapies, and decades from now, physicians might be able to pick and choose from a variety of options that can be tailored for individual patients. “It’s so incredible that we’ve gotten to this point,” he says. “But in 20 years, the CAR T cells we use for patients will look very different from now.”Such modifications to CAR-T-cell therapies are only the beginning, says Vitanza. Researchers are hunting for more ways to supercharge CAR-T-cell therapies, and decades from now, physicians might be able to pick and choose from a variety of options that can be tailored for individual patients. “It’s so incredible that we’ve gotten to this point,” he says. “But in 20 years, the CAR T cells we use for patients will look very different from now.”