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Phase I Clinical Trial of Gene-Edited Cells for Cancer Proves Safe and Durable

illustration of CRISPR concept
CRISPR-Cas9-edited T cells could be used to boost the immune response against cancer. | McGovern Institute for Brain Research at MIT

Following the first U.S. test of CRISPR gene editing in three patients with advanced cancer — designed to test safety — researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies for months, longer than expected.

The results from this Phase 1 clinical trial, published in the February 7 issue of Science, suggest the gene editing approach was not harmful to participants and that the edited cells can go where intended, which until now had been uncertain.

"Before we did this, no one had ever infused CRISPR-edited cells into patients, and we're encouraged by the fact that we could do it safely," said first author Edward Staudtmauer, an oncologist at the University of Pennsylvania and the study's principal investigator.

The findings represent an important step toward the ultimate goal of using gene editing to improve a patient's immune system's ability to attack and kill cancer, a process known as immunotherapy. Researchers will need to see results from larger numbers of patients to determine how effective the treatment is, the authors emphasize.

"The big question that remains unanswered by this study is whether gene-edited, engineered T cells are effective against advanced cancer," write Jennifer Hamilton, of the University of California, Berkeley, and Jennifer Doudna, a leader in CRISPR development also at UC Berkeley, in a related Perspective.

Though one of three patients in the trial saw tumors shrink during the treatment, and they all experienced some stabilization, the edited T cells were far from a complete solution. One patient with multiple myeloma died in December, seven months after receiving the treatment. The two remaining patients have since had their cancer worsen.

This study was restricted to gene editing protocols available in 2016, however, which render gene-edited T cells less effective than they would be using technology available today.

T cells, a type of white blood cell critical to immune system function, naturally fight diseases like cancer, but researchers hope gene editing using CRISPR-Cas9 may be a tool to improve T cells' natural fight, making them more potent. Whether CRISPR-Cas9-edited T cells would be tolerated and survive once reinfused into a human, however, has been unknown. There have been concerns that they would generate an immune response, leading to negative side effects.

Stadtmauer and colleagues sought to test this in three patients in their 60s with advanced blood cancers that didn't respond to standard treatments like chemotherapy and radiation.

The first patient treated had had eight previous courses of chemotherapy and three bone marrow transplants but continued to worsen. "None of the patients had any realistic options with currently FDA approved drugs," said Staudtmauer.

He and colleagues removed T cells from these patients' blood and used CRISPR to delete three genes from the cells that might interfere with the immune system's ability to fight cancer. "With previous technologies," said Staudtmauer, "it was not possible to do extensive genome editing like this."

Next, the researchers used a virus to arm the T-cells to attack a protein typically found on cancer cells called NY-ESO-1.

The researchers then infused the edited cells — about 100 million of each patient's own T cells — back into the patients and monitored the cells' persistence. The cells were taken up by the blood, went where they were supposed to in the immune system, led to no side effects, and could be detected up to nine months after they were infused.

The work builds on earlier T cell advances of pioneering immunotherapy researcher Carl June, a professor of immunotherapy at the University of Pennsylvania, who was also part of this study. It also opens up possibilities for using this approach in solid malignancies like breast, colon and lung cancer, as well as in the blood cancers evaluated here.

The therapy will need to be tested in more patients to better understand possible side effects and the benefit of the engineered T-cells over time.

"The next step will be further engineering these cells and expanding the number of patients treated," said Staudtmauer, who added that the research team was "gratified" by this study's results.