An experimental "off-the-shelf" cell therapy for cancer helped eliminate or reduce disease in more than half of the lymphoma patients infused with higher doses in a clinical trial, a finding that the treatment's owner, CRISPR Therapeutics, says can match up with similar, rival drugs that are more logistically complex.
The trial also showed the treatment so far hasn't caused severe cases of a potentially deadly immune-related condition caused by cancer therapies that are made using a patient's own cells. The results are likely to add fuel an ongoing debate over how effective off-the-shelf therapies — which rely on cells donated by healthy people — might be when compared to the patient-derived versions, such as Novartis' Kymriah and Gilead's Yescarta.
Those products, known as CAR-T therapies, are powerfully effective tools for lymphoma and leukemia patients whose disease has progressed despite several treatments. But the process of manufacturing them is complicated and can take weeks to complete, meaning patients who need treatment might not receive it in time.
CAR-T therapies also have such high rates of an immune response called cytokine release syndrome, or CRS, that patients must remain in or near specialized hospitals to treat them in case the condition arises.
Should CRISPR's therapy, dubbed CTX110, gain approval, it might be able to be used more widely, according to CEO Sam Kulkarni. "With our almost zero CRS rate, this can easily move into community settings," he said in an interview.
The latest findings offer little insight, however, into a question that's been hanging over donor-derived, gene-edited CAR-Ts like CTX110 since last week, when another biotech, Allogene Therapeutics, found a "chromosomal abnormality" in the engineered cells of a study participant. The Food and Drug Administration suspended all of Allogene's trials, an announcement that caused a stock sell-off for many gene editing companies, including CRISPR.
Kulkarni noted that Allogene uses a different technology to engineer cells into a cancer-fighting treatment. "It’s very difficult for us to comment," he said, but "at this point we don’t think it applies quite to us."
CRISPR's study, an early-stage trial named CARBON, aimed to identify a dose of CTX110 that would reduce or eliminate diseased cells without causing unacceptable side effects. The trial tested five different doses and enrolled 27 patients, 26 of whom were treated. One participant didn't receive an infusion because of a case of COVID-19, Kulkarni said.
At the lowest dose, three patients received infusions of 30 million cells and none showed signs that the treatment reduced or eliminated their cancers. Of the 23 patients who receive doses of at least 100 million cells, 14 of them, or 61%, had responded 28 days after treatment. Nine, or 39%, had a complete response, which according to CRISPR means all symptoms and diseased tissue were eliminated.
The drug's effectiveness increased with dosage, with six of eight patients who received 6 billion cells showing some level of response, the company said.
CRISPR's treatment doesn't, however, appear to be as durable as its CAR-T counterparts — an observation that's been seen in tests of other off-the-shelf cell therapies. Of the nine patients driven into remission, four remained disease free six months later, a rate of 21% across all treated patients who have been followed for six months or more, according to CRISPR. Treatments like Kymriah, Gilead's Yescarta and Bristol Myers Squibb's Breyanzi had six-month complete response rates of 29% to 40% in the pivotal studies that led to their approvals.
Analysts and investors appeared to be hoping for signs of a stronger response from CTX110. Shares fell 7% in early trading Tuesday morning, the first session since CRISPR detailed the data Monday afternoon, and were changing hands at around $95.
Because they have not been tested against each other in a trial, it's not exactly known how CRISPR's and other cell therapies stack up. Kulkarni, though, argued the benefits of CAR-T treatments may be exaggerated because their trial results don't include patients who couldn't get treated.
Manufacturing failures or disease progression while waiting for treatment can prevent people from accessing CAR-T outside of clinical trials. But in Novartis' key trial, known as Juliet, those types of patients — 54 of the 165 who were enrolled — weren't included in the study's analysis.
Off-the-shelf CAR-T, by contrast, is meant to be more reliable. All but one patient enrolled in CARBON received treatment.
On the safety side, meanwhile, all 13 cases of CRS were judged to be mild enough that patients only needed low-level oxygen support, not medication to raise their blood pressures. One severe neurological side was recorded in a patient with an established chronic nervous system infection.
CRISPR now plans to ask the Food and Drug Administration to expand the study and turn it into a late-stage trial that could support an approval filing.
Because one dose of its off-the-shelf treatment doesn't appear to last as long as CAR-T therapies but appears safer, the company wants clearance to give patients a second dose to boosts its effects. This approach might overcome some of the therapy's shortcomings, and help differentiate it from patient-derived treatments, Kulkarni said.
"We can ensure that a greater fraction of patients get to complete response," he said, and also that "a greater proportion of patients who get to complete response remain in complete response."
Benjamin Burnett, an analyst at Stifel, wrote in an Oct. 13 note to clients that the durability of donor-derived CAR-T therapies needs to match their patient-derived rivals before doctors will use them. "In our view, single doses fall short of this," he wrote, "but there is a chance that subsequent doses could push the efficacy envelope."
This story has been updated with the Oct. 13 share price and analyst comment.