First proposed human test of CRISPR passes initial safety review

A cancer study that would represent the first use of CRISPR in people passed a key safety review on June 21st (Science, 2016). The proposed clinical trial, in which researchers would use CRISPR to engineer immune cells to fight cancer, won approval from the Recombinant DNA Advisory Committee (RAC) at the US National Institutes of Health.

Although other forms of gene editing have already been used to treat disease in people, the CRISPR trial would break new ground by modifying three genes at once, which has not been easy to do until now. The study has also grabbed attention because, as first reported by the MIT Technology Review, former Facebook president Sean Parker’s $250m Parker Institute for Cancer Immunotherapy, set up in April, will fund the trial, which currently has no specific budget (Nature, 2016).

“Last year’s excitement over CRISPR was in anticipation of this,” says Dean Anthony Lee, an immunologist at MD Anderson Cancer Center in Houston, Texas, and one of the three RAC members who reviewed the proposal. He said CRISPR makes genome engineering easy enough that such trials can move forward quickly.

Another member of the RAC review panel, clinical oncologist Michael Atkins of Georgetown University in Washington, DC, said “It’s an important new approach. We’re going to learn a lot from this. And hopefully it will form the basis of new types of therapy.”

“Cell therapies [for cancer] are so promising but the majority of people who get these therapies have a disease that relapses,” said study leader Edward Stadtmauer, a physician at the University of Pennsylvania (UPenn). He said gene editing could improve such treatments and eliminate some of their vulnerabilities to cancer and the body’s immune system.

The proposed CRISPR trial builds off the pioneering efforts of Carl June and others at UPenn to genetically modify a cancer patient’s own immune cells, specifically a class known as T cells, to treat leukaemia and other cancers.

A UPenn-led team wants to remove T cells from patients and use a harmless virus to give the cells a receptor for NY-ESO-1, a protein that is often present on certain tumours but not on most healthy cells. The modified T cells are then reinfused back into a patient and, if all goes well, attack the person’s NY-ESO-1–displaying tumours. The UPenn team has already tested this strategy in a small clinical trial for multiple myeloma. But although most patients’ tumours initially shrank, the reintroduced T cells eventually became less effective and stopped proliferating.

To boost the staying power of the engineered T cells, the UPenn group wants to use CRISPR to disrupt the gene for a protein called PD-1. The protein sits on the surface of T cells and helps dampen the activity of the cells after an immune response, but tumours have found ways to hide from T cell attack by flipping on the PD-1 switch themselves. Drugs that block PD-1 eliminate this immune suppression and have proven to be a promising immunotherapy cancer treatment.

Carl June’s team also wants to knock out the genes that code for the two proteins that make up a T cell’s primary receptor so that the engineered NS-ESO-1 receptor will be more effective. To do this, they will introduce into the T cells so-called guide RNAs, which tell CRISPR’s DNA-snipping enzyme, Cas9, where to cut the genome.

The two year trial will treat eighteen people with myeloma, sarcoma, or melanoma who have stopped responding to existing treatments at three sites that are members of the Parker Institute; UPenn, the University of California, San Francisco and the University of Texas MD Anderson Cancer Center in Houston. Carl June pointed out to RAC that his team already has experience with gene editing. In 2014, Carl June led a trial using a different gene-editing system called zinc-finger nuclease. His group took blood from twelve people with HIV and removed the gene that encodes a protein on T cells that the virus targets. They hoped that this would prevent infection of the cells. The results were encouraging, and the technique is now being used in clinical trials for several other conditions.

To confirm that, researchers conducting the CRISPR trial will look for signs of an immune reaction to the Cas9 enzyme, which comes from a bacterium. They will also look for evidence that it has made cuts in wrong places, potentially creating or triggering a cancer gene. When the UPenn team recently used CRISPR to edit T cells from healthy donors as a test run, they checked the 148 genes they most feared Cas9 would mistakenly slice and only found one cut in a harmless location. For the CRISPR trial, the team will do various tests to watch for uncontrolled growth of the modified T cells. Because they are editing three genes, one RAC member also noted, the team should watch for large swapped chunks of chromosomes.

Another concern raised by several RAC members is that Carl June, who would not treat the cancer patients but would serve as the trial’s scientific adviser, and UPenn have a financial interest in the trial. Carl June has ties to Novartis, holds patents on T cell technologies, and could stand to benefit from the success of this trial. He declined to give details on the exact nature of his conflicts of interest, but said his university is taking steps to manage it, such as preventing him from being involved in selecting patients.

Several RAC reviewers suggested that UPenn not be allowed to recruit patients at all and to leave it to other institutions: this language did not make it into their final approval. Some on the panel suggested they were particularly sensitive about such concerns given that it was at UPenn in 1999 Jessie Gelsinger died aged eighteen in a gene therapy trial, setting the field back for years. “Penn does have an infamous history in this regard,” said biomedical ethicist and RAC member Lainie Ross of the University of Chicago.

However, others on the panel noted that the university could take various steps to mitigate the conflict of interest, for example by recusing Carl June from specific tasks. UPenn itself should decide whether it can directly treat patients or merely supply the modified T cells to other sites for the trial, RAC concluded. Ultimately, RAC members voted unanimously, with one abstention, to approve the trial.

Although RAC endorsement is a big step, the researchers must now seek approval from their own institutions’ ethics boards and the FDA.

Others trials are not far behind. Many thought the Cambridge, Massachusetts–based biotech company Editas Medicine would conduct the first CRISPR clinical trial, it has announced plans to use CRISPR to treat an inherited eye disease in 2017, but RAC has not yet reviewed a proposal from the company.

Last week, researchers at Great Ormond Street Hospital for Children in London began a safety study with 10 children using a similar technique called TALENS. Instead of using a patient’s own cells, the system uses T cells from a donor that have been edited to remove genes that would cause the patient’s body to reject them. The gene editing then directs the T cells to attack the cancer and protects the cells from damage by other immunotherapy drugs.

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