美国国家公共电台 NPR--CRISPR gene-editing may boost cancer immunotherapy, new study finds

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Transcript¹

Katie Pope Kopp went through round after round of chemotherapy and a stem cell transplant to treat her non-Hodgkin lymphoma. But nothing could beat it.

"I went back to get a PET scan in May of 2020, and that's when they found that my non-Hodgkin's had blown back up, which was very disappointing," says Kopp, 64, of Parkville, Mo. She was originally diagnosed five years ago.

Victor Bartolome suffered through decades of chemotherapy and a stem cell transplant, too, to keep his blood cancer at bay. Eventually, his doctors told him he had run out of options.

"That was devastating². Imagine having what you think is your last hope pulled out from under you," says Bartolome, 74, of Santa Barbara, Calif.

But then Kopp and Bartolome heard about something new: In the last few years, some doctors have started using the gene-editing technique CRISPR to try to modify cells of the immune system to treat cancers like theirs.

Kopp jumped at the chance to volunteer for a study testing the approach, even though she says she's a tarot card reader who long relied on homeopathy instead of mainstream⁴ medicine.

"I'm like: 'Yeah. Sign me up. I'll be your guinea pig,' " she says, laughing.

Bartolome, a former NBA basketball player, was game, too.

"It sounded like something from a science fiction movie. I thought that was pretty cool," Bartolome says.

Today, after getting the experimental treatment more than a year ago, both remain in remission, raising hopes the gene-editing technique may offer new hope to at least some cancer patients. On Monday, Kopp's doctor presented at a research conference the latest encouraging data on 32 patients. NPR got exclusive access to tell the stories of Bartolome and Kopp.

"It's just amazing," Kopp says of her experience.

CRISPR, which allows scientists to make very precise changes in DNA⁵ much more easily than ever before, had already shown promise for a variety of genetic⁶ disorders⁷, including sickle⁸ cell disease. But attempts to use CRISPR to treat other diseases have produced some disappointments recently.

Using CRISPR might make immunotherapy better for a broader set of cancers and patients

Kopp and Bartolome volunteered for studies testing CRISPR to advance one of the most exciting developments in cancer treatment in decades: known as CAR T-cell therapies. These are called "living drugs" because they're living cells of the immune system, taken from cancer patients and then reinfused after being genetically⁹ engineered in the lab to attack the patient's tumors.

"In contrast to drugs, this is a living therapy," says Dr. Joseph McGuirk, an oncologist at the University of Kansas, who treated Kopp. "You're injecting into your patient a drug that is alive, that can persist for weeks to months and sometimes beyond that — for years."

McGuirk and others are hoping CRISPR can make better CAR T-cell living drugs, such as versions that are more potent¹⁰ and effective at treating more common cancers.

The approach tested on Kopp and Bartolome is known as "off-the-shelf" CAR-T. It's made in huge batches¹¹ that would be ready right away for any patient, rather than having to wait weeks or even months for bespoke¹² CAR T-cells made for each patient from their own cells. These off-the-shelf therapies could help patients whose own immune cells are too damaged, or are too sick to wait.

"These patients have aggressive diseases — don't have time on their side. And so some patients will become too sick to receive the therapy, or die before the therapy can be generated in the laboratory," McGuirk says.

Off-the-shelf CAR T-cell treatments could also be much less expensive than custom-made.

"I'm totally excited about this. This would be a game-changer that way, with a total new approach," says Dr. Carl June is a CAR T-cell pioneer at the University of Pennsylvania who is not involved in the studies that included Kopp and Bartolome.

How it works

To create these cells, doctors take immune system cells known as T cells from a healthy donor¹³ and use CRISPR to re-program the T cells to do three things: Leave alone the healthy cells in a patient's body; hide from the recipient's own immune system, and zero in on — and destroy — whatever cancer the patient is fighting.

"The T cell sucks up against the cancer cell, releases molecules¹⁴ that essentially¹⁵ punch holes in the cancer, and release small enzymatic¹⁶ machinery¹⁷ — you can think of them as Pac-Men," McGuirk says. "They race through those holes and they go in and they chop the DNA of the cancer cell, and the cancer cell dies."

On Monday, McGuirk presented the latest results of his research at an American Society of Hematology meeting in New Orleans. McGuirk reported that the approach shrank tumors in 67% of 32 patients with the same kind of cancer Kopp had. Forty-percent experienced a complete remission of their cancer — including Kopp, who's shown no evidence of malignancy for more than two years.

"This is the most exciting — just extra-extraordinary — time in my entire career," McGuirk says. "And I've always been excited by the work we've been doing. But this is unprecedented¹⁸."

The study Bartolome volunteered for, involving 18 patients, has produced similar results.

"This is enormous," says Dr. Swaminathan Iyer, an oncologist at the University of Texas M.D. Anderson Cancer Center in Houston, who's leading that research. Both studies are being sponsored by CRISPR Therapeutics in Boston. "We have not had a therapy like this of such promise in T cell lymphomas," Iyer says.

"The prospects¹⁹ are much brighter than anyone could have dreamed of 10 years ago," agrees Fyodor Urnov, a gene-editing scientist at the University of California, Berkeley, who was not involved in the research. "This field is progressing remarkably²⁰ fast."

Drawbacks to 'off-the-shelf' CAR T-cell treatments remain

But not all researchers are as enthusiastic about the promise of off-the-shelf CAR T-cell treatments. Some point out that this version of the more generic²¹ therapy doesn't appear to last as long, and may not be as effective, as the original versions, which rely on a patient's own cells.

"That's kind of like the main problem we have here. It is faster. It is more convenient logistically. Perhaps less expensive. But then you have a fundamental issue of persistence," says Dr. James Kochenderfer, who is doing similar research at the National Cancer Institute. "That's a fundamental problem that you cannot completely overcome, no matter what you do."

Dr. Michel Sadelain at Memorial Sloan Kettering Cancer Center in New York agrees with Kochenderfer that there's room for improvement.

"The results so far are encouraging," Sadelain says. "However, the rate of responses is not as good as you obtain with a patient's own cells. So we need further investigation²²."

McGuirk and others acknowledge that more research is needed involving more patients to figure out just how well the off-the-shelf approach works, how long it lasts, and how to make the cells last longer and work better.

"When you consider the overwhelming number of these patients would have died, that's a big advance," McGuirk says. "None of us are satisfied with that. We need to do better, better better."

For example, he says, some of the shortcomings might be overcome by giving patients more than one infusion²³.

For their part, Kopp and Bartolome are thrilled.

Kopp's been in remission for more than two years.

"You know, I've been a homeopathic all my life, pretty much, and now I joke ... 'I'm genetically modified,' " Kopp says. "But this little vial of cells can change my life? Wow. Just, truly, medical miracle."

Victor and Barbara Bartolome in Santa Barbara on Thanksgiving Day. A former pro³ basketball player for the Golden State Warriors²⁴, Victor volunteered for a study testing CRISPR's capacity to help fight cancer. He says he'll never forget the day, more than a year ago, when doctors told him they could no longer find any trace of the malignancy in his body.

Barbara Bartolome

Bartolome say he'll never forget the day the doctors told him they couldn't find a trace of cancer in his body. That was more than a year ago.

"It was a life-changing event. And I was bubbling up inside, that's for sure," he says. "That was a great day. And every day since then I just thank my lucky stars."

1 transcript   

n.抄本，誊本，副本，肄业证书

参考例句：

• A transcript of the tapes was presented as evidence in court.一份录音带的文字本作为证据被呈交法庭。
• They wouldn't let me have a transcript of the interview.他们拒绝给我一份采访的文字整理稿。

2 devastating   

adj.毁灭性的，令人震惊的，强有力的

参考例句：

• It is the most devastating storm in 20 years.这是20年来破坏性最大的风暴。
• Affairs do have a devastating effect on marriages.婚外情确实会对婚姻造成毁灭性的影响。

3 pro   

n.赞成，赞成的意见，赞成者

参考例句：

• The two debating teams argued the question pro and con.辩论的两组从赞成与反对两方面辩这一问题。
• Are you pro or con nuclear disarmament?你是赞成还是反对核裁军？

4 mainstream   

n.（思想或行为的）主流；adj.主流的

参考例句：

• Their views lie outside the mainstream of current medical opinion.他们的观点不属于当今医学界观点的主流。
• Polls are still largely reflects the mainstream sentiment.民调还在很大程度上反映了社会主流情绪。

5 DNA   

(缩)deoxyribonucleic acid 脱氧核糖核酸

参考例句：

• DNA is stored in the nucleus of a cell.脱氧核糖核酸储存于细胞的细胞核里。
• Gene mutations are alterations in the DNA code.基因突变是指DNA密码的改变。

6 genetic   

adj.遗传的，遗传学的

参考例句：

• It's very difficult to treat genetic diseases.遗传性疾病治疗起来很困难。
• Each daughter cell can receive a full complement of the genetic information.每个子细胞可以收到遗传信息的一个完全补偿物。

7 disorders   

n.混乱( disorder的名词复数 )；凌乱；骚乱；（身心、机能）失调

参考例句：

• Reports of anorexia and other eating disorders are on the increase. 据报告，厌食症和其他饮食方面的功能紊乱发生率正在不断增长。 来自《简明英汉词典》
• The announcement led to violent civil disorders. 这项宣布引起剧烈的骚乱。 来自《简明英汉词典》

8 sickle   

n.镰刀

参考例句：

• The gardener was swishing off the tops of weeds with a sickle.园丁正在用镰刀嗖嗖地割掉杂草的顶端。
• There is a picture of the sickle on the flag. 旗帜上有镰刀的图案。

9 genetically   

adv.遗传上

参考例句：

• All the bees in the colony are genetically related. 同一群体的蜜蜂都有亲缘关系。
• Genetically modified foods have already arrived on American dinner tables. 经基因改造加工过的食物已端上了美国人的餐桌。 来自英汉非文学 - 生命科学 - 基因与食物

10 potent   

adj.强有力的，有权势的；有效力的

参考例句：

• The medicine had a potent effect on your disease.这药物对你的病疗效很大。
• We must account of his potent influence.我们必须考虑他的强有力的影响。

11 batches   

一批( batch的名词复数 )； 一炉； （食物、药物等的）一批生产的量； 成批作业

参考例句：

• The prisoners were led out in batches and shot. 这些囚犯被分批带出去枪毙了。
• The stainless drum may be used to make larger batches. 不锈钢转数设备可用来加工批量大的料。

12 bespoke   

adj.（产品）订做的；专做订货的v.预定( bespeak的过去式 )；订（货）；证明；预先请求

参考例句：

• His style of dressing bespoke great self-confidence. 他的衣着风格显得十分自信。
• The haberdasher presented a cap, saying,"Here is the cap your worship bespoke." 帽匠拿出一顶帽子来说：“这就是老爷您定做的那顶。” 来自辞典例句

13 donor   

n.捐献者；赠送人；(组织、器官等的)供体

参考例句：

• In these cases,the recipient usually takes care of the donor afterwards.在这类情况下，接受捐献者以后通常会照顾捐赠者。
• The Doctor transplanted the donor's heart to Mike's chest cavity.医生将捐赠者的心脏移植进麦克的胸腔。

14 molecules   

分子( molecule的名词复数 )

参考例句：

• The structure of molecules can be seen under an electron microscope. 分子的结构可在电子显微镜下观察到。
• Inside the reactor the large molecules are cracked into smaller molecules. 在反应堆里，大分子裂变为小分子。

15 essentially   

adv.本质上，实质上，基本上

参考例句：

• Really great men are essentially modest.真正的伟人大都很谦虚。
• She is an essentially selfish person.她本质上是个自私自利的人。

16 enzymatic   

adj. 酶的

参考例句：

• This chromoprotein has also been endowed with enzymatic properties. 这种色素蛋白也具有酶的特性。
• It is of profound interest to elucidate the enzymatic activities in soil. 阐明土壤中酶的活性是有深远意义的。

17 machinery   

n.(总称)机械，机器；机构

参考例句：

• Has the machinery been put up ready for the broadcast?广播器材安装完毕了吗？
• Machinery ought to be well maintained all the time.机器应该随时注意维护。

18 unprecedented   

adj.无前例的，新奇的

参考例句：

• The air crash caused an unprecedented number of deaths.这次空难的死亡人数是空前的。
• A flood of this sort is really unprecedented.这样大的洪水真是十年九不遇。

19 prospects   

n.希望，前途(恒为复数)

参考例句：

• There is a mood of pessimism in the company about future job prospects. 公司中有一种对工作前景悲观的情绪。
• They are less sanguine about the company's long-term prospects. 他们对公司的远景不那么乐观。

20 remarkably   

ad.不同寻常地，相当地

参考例句：

• I thought she was remarkably restrained in the circumstances. 我认为她在那种情况下非常克制。
• He made a remarkably swift recovery. 他康复得相当快。

21 generic   

adj.一般的，普通的，共有的

参考例句：

• I usually buy generic clothes instead of name brands.我通常买普通的衣服，不买名牌。
• The generic woman appears to have an extraordinary faculty for swallowing the individual.一般妇女在婚后似乎有特别突出的抑制个性的能力。

22 investigation   

n.调查，调查研究

参考例句：

• In an investigation,a new fact became known, which told against him.在调查中新发现了一件对他不利的事实。
• He drew the conclusion by building on his own investigation.他根据自己的调查研究作出结论。

23 infusion   

n.灌输

参考例句：

• Old families need an infusion of new blood from time to time.古老的家族需要不时地注入新鲜血液。
• Careful observation of the infusion site is necessary.必须仔细观察输液部位。

24 warriors   

武士，勇士，战士( warrior的名词复数 )

参考例句：

• I like reading the stories ofancient warriors. 我喜欢读有关古代武士的故事。
• The warriors speared the man to death. 武士们把那个男子戳死了。