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First CRISPR trial in humans is reported to start next monthhttps://www.statnews.com/2016/07/21/crispr-experiment-humans/
Scientists in China plan to use the genome-editing technology CRISPR-Cas9 in patients as early as next month, Nature reported on Thursday. If they go ahead, it would be the first time people would be injected with cells whose DNA has been altered by CRISPR.
A US proposal to run a similar study received approval by a federal ethics and safety panel last month, but it faces months of additional regulatory hurdles before it can go ahead by the end of 2016 at the earliest. The Chinese scientists, led by oncologist Lu You of Sichuan University’s West China Hospital in Chengdu, received approval from the hospital’s review board on July 6, Nature reported, and plan to treat their first patient in August.
Both the US and Chinese scientists would use CRISPR to edit immune-system T cells in patients with cancer in an effort to make those cells destroy malignant cells.
Like the proposed US study, Lu’s would start by removing T cells from the blood of patients, in this case those with non-small cell lung cancer that has spread to distant sites in the body and no longer responds to treatment. Using CRISPR, his team would delete a gene for a molecule called PD-1. That molecule is a receptor on the surface of T cells, and is the Achilles’ heel of the immune system’s cancer-fighting efforts: Many tumors produce molecules that slip into PD-1 and turn off the T cell as effectively as a key turning off a car ignition.
Drugs that block this process, including Merck’s Keytruda (the drug that has successfully treated former President Jimmy Carter) and Bristol-Myers Squibb’s Opdivo, have recently raised hopes that the immune system can be unleashed on more cancers.
The CRISPR’d T cells would be coaxed to multiply in lab dishes, and then examined to make sure that only the PD-1 gene has been altered. (One concern about CRISPR is that it has “off-target effects,” deleting or changing genes it isn’t supposed to touch.)
If Lu’s team determines that the T cells are missing only their PD-1 gene, researchers would infuse the edited cells back into patients, where, if everything goes well, the T cells would attack the tumors. The trial will include 10 patients to start, with different doses of the cells to assess safety, according to Nature.
Last year, the Food and Drug Administration approved both Keytruda and Opdivo for non-small cell lung cancer, based on human studies showing that blocking PD-1 indeed frees T cells to attack those tumors. That suggests that a genome-editing approach to achieve the same molecular goal might also be successful.
CRISPR testing in China has previously leapfrogged that in other countries. Last year, for instance, scientists in China became the first to use CRISPR to edit the DNA of human embryos. (The embryos were nonviable.)
Genome-editing technology has raised the greatest concerns over its possible use in eggs, sperm, or early human embryos, called germline editing. Critics fear that could lead to “designer babies” with the altered DNA inherited by offspring. In April, Xiaomei Zhai of Peking Union Medical College told a US National Academy of Sciences panel on genome editing that “if the risk-benefit ratio is acceptable, a total ban on germline gene editing is not ethically justifiable.”
Chinese scientists to pioneer first human CRISPR trial Gene-editing technique to treat lung cancer is due to be tested in people in August.
21 July 2016
Nature
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Genes in immune cells will be edited in an effort to turbocharge their attack on tumours.
Chinese scientists are on the verge of being first in the world to inject people with cells modified using the CRISPR–Cas9 gene-editing technique.
A team led by Lu You, an oncologist at Sichuan University’s West China Hospital in Chengdu, plans to start testing such cells in people with lung cancer next month. The clinical trial received ethical approval from the hospital's review board on 6 July.
“It’s an exciting step forward,” says Carl June, a clinical researcher in immunotherapy at the University of Pennsylvania in Philadelphia.
There have been a number of human clinical trials using an alternative gene-editing technique, including one led by June, that have helped patients combat HIV. June is also a scientific adviser on a planned US trial that would also use CRISPR–Cas9-modified cellsfor the treatment of cancer.
Last month, an advisory panel of the US National Institutes of Health (NIH) approved that project. But the trial also requires a green light from the US Food and Drug Administration (FDA) and a university review board. The US researchers have said they could start their clinical trial by the end of this year.
Ineffective chemoThe Chinese trial will enrol patients who have metastatic non-small cell lung cancer and for whom chemotherapy, radiation therapy and other treatments have failed. “Treatment options are very limited,” says Lu. “This technique is of great promise in bringing benefits to patients, especially the cancer patients whom we treat every day.”
Lu’s team will extract immune cells called T cells from the blood of the enrolled patients, and then use CRISPR–Cas9 technology — which pairs a molecular guide able to identify specific genetic sequences on a chromosome with an enzyme that can snip the chromosome at that spot — to knock out a gene in the cells. The gene encodes a protein called PD-1 that normally acts as a check on the cell’s capacity to launch an immune response, to prevent it from attacking healthy cells.
The gene-edited cells will then be multiplied in the lab and re-introduced into the patient’s bloodstream. The engineered cells will circulate and, the team hopes, home in on the cancer, says Lu. The planned US trial similarly intends to knock out the gene for PD-1, and it will also knock out a second gene and insert a third before the cells are re-introduced into the patient.
Last year, the FDA approvedfor use against lung cancertwo antibody-based therapies that block PD-1. But it is difficult to predict for any given patient to what extent these antibodies will block PD-1 and activate the immune response.
By contrast, knocking out the gene blocks PD-1 with greater certainty, while multiplying the cells increases the chance of a response. “It will be much more powerful than the antibodies," says Timothy Chan, who does clinical research in immunotherapy at Memorial Sloan Kettering Cancer Center in New York City.
Validated cellsIt is well known that CRISPR can result in gene edits at the wrong place in the genome, with potentially harmful effects. Chengdu MedGenCell, a biotechnology company and a collaborator on the trial, will validate the cells to ensure that the correct genes are knocked out before the cells are re-introduced into the patients, says oncologist Lei Deng of West China Hospital, who is a member of Lu’s team.
Because the technique targets T cells, which are involved in various kinds of immune responses, in a non-specific way, Chan worries that the approach might induce an excessive autoimmune response in which the cells would start attacking the gut, or adrenaline glands or other normal tissue. “All the T cells — everything will be active. That will be a concern,” says Chan.
He suggests, instead, that the team take T cells from the site of the tumour, because they would already be specialized for attacking cancer. But Deng says that the lung-cancer tumours targeted by their trial are not easily accessible. He also says that the team is reassured by the FDA-approved antibody therapies, which did not show a high rate of autoimmune response.
The phase I trial is designed foremost to test whether the approach is safe. It will examine the effects of three different dosage regimens on ten people, and, Deng says, the team plans to proceed slowly, increasing the dosage gradually and starting with just one patient, who will be monitored closely for side effects. But the researchers will also closely watch markers in the blood that would indicate that the treatment is working.
Fast reputationLu says that the review process, which took half a year, required that the team invest a lot of time and human resources, including close communication with the hospital’s internal review board (IRB). “There was a lot of back and forth,” he says. The NIH’s approval of the other CRISPR trial “strengthened ours and our IRB’s confidence in this study”, he adds.
China has had a reputation for moving fast — sometimes too fast — with CRISPR, says Tetsuya Ishii, a bioethicist at Hokkaido University in Sapporo, Japan.
According to Lu, his team was able to move fast because they are experienced with clinical trials of cancer treatments.
June is not surprised that a Chinese group would jump out in front on a trial such as this: “China places a high priority on biomedical research,” he says.
Ishii notes that if the clinical trial begins as planned, it would be the latest in a series of firsts for China in the field of CRISPR gene editing, including the first CRISPR-edited human embryos, and the first CRISPR-edited monkeys. “When it comes to gene editing, China goes first,” says Ishii.
“I hope we are the first," says Lu. "And more importantly, I hope we can get positive data from the trial.”
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发表于 2016-8-9 07:00