If all goes as planned, the first clinical trial in the United States testing CRISPR against cancer by altering the DNA of tumor cells inside patients could begin recruiting participants next year, the scientist leading the effort told STAT.

Seventeen studies using CRISPR to treat cancer have been listed on the U.S. registry of clinical trials, but most of those use this genome editing technology to engineer immune cells to attack tumors. That approach, including a pioneering one led by scientists at the University of Pennsylvania, is essentially just a variation on the production of CAR-T cells: CRISPR edits T cells that are isolated from blood that’s been removed from patients, and then the T cells are infused back into the patient. And although researchers in China are rumored to be testing a more direct use of CRISPR against cancer, except for one study using CRISPR to knock out viruses that cause cervical cancer, they have not made details of their plans public.

The Gene Editing Institute at Christiana Care Health System, a nonprofit, private community (as opposed to academic) medical system headquartered in Delaware, is preparing to seek regulatory approval for a much bolder CRISPR cancer study. If it receives the OK from the Food and Drug Administration, which it plans to request in the next few months, it would recruit six to 10 patients with late stage non-small-cell lung cancer and test whether using CRISPR to disable a particular gene would allow standard chemotherapy to work better and longer, ideally buying patients a little more time.


“We have to be modest,” said Eric Kmiec, director of Christiana’s Gene Editing Institute. “The goal is to give them a few more months of life, but we hope there will be additional benefits.”

His target: a gene called NRF2 (nuclear factor erythroid 2-related factor). It produces a protein called a transcription factor, which activates some 200 genes that, among other things, pump alien chemicals out of tumor cells. Those chemicals include the chemotherapy drugs cisplatin and carboplatin, so lung cancer cells become resistant to them.

“NRF2 is a major culprit in fighting off cisplatin and carboplatin,” Kmiec said. “And expression of NRF2 increases as lung cancer goes from stage 1 to 2 to 3 to 4,” advancing first to the lymph nodes and then to distant organs. “We thought it would make a good target.”

Studies of cells growing in lab dishes suggest that knocking out NRF2 makes tumor cells proliferate more slowly and become more vulnerable to chemo.

Kmiec and his colleagues have not yet determined how to deliver CRISPR to tumor cells, a challenge for the entire field. They will either inject CRISPR directly into lung tumors or administer it via infusion into the blood, packaged in adeno-associated viruses (AAVs). One AAV “serotype” makes a beeline for lung cells, including those that have spread beyond the lung, so systemic delivery holds out more hope of attacking cancer metastases.

“We have to figure out the delivery mechanism before we file” for FDA approval of a clinical trial, Kmiec said. Christiana is working with regulatory consultant Synchrogenix, a division of Certara, to finalize its FDA filing.

One reason to believe the edit will hit its target and nothing else is that cells with high expression of NRF2 have a little chunk of DNA that serves as a roadside beacon for CRISPR. Healthy cells lack it. Called a PAM sequence, it should ensure that CRISPR disables NRF2 only in tumor cells and not normal ones.

Because the trial will recruit patients with lung cancer so advanced (stage 3 or 4) they have at most six months to live, Kmiec hopes that regulators will demand fewer guarantees of safety. For instance, there have been concerns that CRISPR’d cells might be prone to developing new cancers decades hence. But that might not be relevant to patients with almost no chance to live that long. Exactly what safety assurances the FDA will require, however, is unclear.

“I think we’ll be underway in 18 months,” Kmiec said, “but it might be earlier.”

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