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Immune cells (brown) attack a cancer cell. Using CRISPR could make the immune cells more potent.

STEVE GSCHMEISSNER/SCIENCE SOURCE

Cutting-edge CRISPR gene editing appears safe in three cancer patients

Launching a new chapter in the fast-moving cancer immunotherapy field, scientists have blended two cutting-edge approaches: CRISPR, which edits DNA, and T cell therapy, in which sentries of the immune system are exploited to destroy tumors. Two women and one man, all in their 60s—one with sarcoma and two with the blood cancer multiple myeloma—received CRISPR-altered versions of their own cells last year, researchers report online in Science this week.

For these pioneers, the benefits were limited: One has since died, and the disease has worsened in the others. But the clinical trial, which underwent years of regulatory scrutiny, wasn’t designed to try to cure cancer, says Carl June, a cancer researcher at the University of Pennsylvania (UPenn) who co-led the work. Rather, its goal was to show that the strategy appeared feasible and safe.

By that measure, scientists agree, it succeeded. “This is a Rubicon that has been decisively crossed,” says Fyodor Urnov, a genome editor at the University of California (UC), Berkeley. The study, he says, the first of its kind in the United States, answers “questions that have frankly haunted the field.”

The researchers used CRISPR alongside another strategy that incorporates new DNA into immune cells. June’s team helped pioneer that strategy in 2010, when it added DNA to T cells from three men with chronic leukemia and returned those cells to the patients. The results were remarkable: Two men are still alive and healthy today. Others were testing the same approach, called CAR-T cell therapy—after the inserted chimeric antigen receptor gene that helps the infused T cells latch onto and destroy cancer cells with a specific protein on their surface. Two CAR-T cell therapies are now approved for patients with leukemia and lymphoma.

But with time, the therapy’s limitations have come into focus. Not every cancer patient is helped, and even those who are can suffer a relapse, says Edward Stadtmauer, who treats blood cancers at UPenn and co-led the new study. And solid tumors like those in the brain and pancreas have proved tough to treat.

Using CRISPR to knock out selected genes while also adding DNA, it was hoped, might make T cells even more powerful and persistent. But CRISPR brought its own uncertainties. Lab studies have revealed “off-target” effects, in which unintended DNA gets modified. No one knew whether T cells with sliced and diced genes could even survive in the human body. Last year, Vertex Pharmaceuticals and CRISPR Therapeutics announced that two patients treated for inherited blood diseases with CRISPR-edited cells were doing well. But details were sparse.

June, Stadtmauer, and their colleagues began by hunting for patients whose tumors produced a protein called NY-ESO-1, a target for the gene the researchers would add to their T cells. The patients also needed to carry a specific version of human leukocyte antigen, an immune gene complex that could help the infused T cells flourish. The four patients who qualified were all extremely ill, as is the norm for such a novel therapy. A woman with multiple myeloma had undergone three bone marrow transplants. Another, in her late 30s with sarcoma, became too sick to treat while her cells were being prepped in the lab, a process that takes 4 to 6 weeks. She entered hospice care and died.

To try to rev up the patients’ T cells against their disease, the scientists used CRISPR to knock out two genes that encode what’s known as the T cell receptor. The group also crippled a third gene, for a protein called PD-1. PD-1 puts the brakes on immune responses, and eliminating its effects, June’s team theorized, might enrich the T cells’ powers. Then, they inserted the gene for a different T cell receptor that would target NY-ESO-1.

Intensive monitoring of the patients, including blood draws to study their altered T cells, confirmed that CRISPR had left some off-target changes. But they were few, and the number of cells with these unintended DNA changes faded over time. Encouragingly, the CRISPR-edited cells persisted at least 9 months—versus about 2 months in comparable CAR-T cell therapy studies. Imaging showed “beautiful, healthy T cells,” June says, that in lab studies beat back cancer months after they’d been infused.

But in patients, outcomes were modest. The best response was in the sarcoma patient, whose primary tumor shrank, though his cancer later progressed. “It wasn’t like you turned off those genes and those T cells started doing things that were amazing,” says Antoni Ribas, an oncologist at UC Los Angeles. Ribas, June, and others offer potential reasons, including the small number of patients treated, possible limitations of NY-ESO-1 as a target—selected in part for its safety record—and the failure to knock out all three genes in many of the cells.

Some of the authors are working with companies to commercialize the method. But much experimentation lies ahead. “This whole area is just teeming with different ideas,” Stadtmauer says. A handful of other trials, including several in China, are offering CRISPR-modified cells to patients with cancer or other diseases. A company called PACT Pharma, which Ribas helped found, is running a trial that uses CRISPR to target gene mutations within solid tumors.

What June’s group offers is “a needed start” for giving patients CRISPR-edited T cells, Ribas says. From now on, he adds, “It’s going to be easier—because they did it first.”