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A Slower, Gentler CAR T-Cell Therapy? USC Says a Small Study Shows It Could Work

Mary Caffrey
Modifications to the engineering of the chimeric antigen receptor (CAR) mean that the patient produces fewer cytokines and has time to clear them before they build up in the bloodstream.
For patients with certain forms of lymphoma and leukemia who have run out of options, chimeric antigen receptor (CAR) T-cell therapy has been described as a miracle: For some, like Emily Dumler, who was treated at MD Anderson, CAR T-cell therapy “gave me my life back” after 6 rounds of chemotherapy had failed.

But even when it works, the treatment that harvests a patient’s T cells and engineers them to attack cancer in the body is far from benign. It’s been described as a bomb going off in the body, or “the worst flu you could get.” The cognitive effects and the symptoms of cytokine release syndrome (CRS) can be severe and even life-threatening. Adverse events are one reason that while the cost of treatments themselves are $373,000 or $495,000, depending on the indication, the full cost of care can be $800,000 to $1.5 million.

However, researchers at the University of Southern California (USC) say they’ve come up with a slower-moving and significantly less toxic version of an anti-CD19 CAR T-cell treatment that brought complete remission in 6 of 11 patients with lymphoma who received the same dose in the phase 1 trial, which tested several different doses in 25 patients. According to the report3 in the journal Nature Medicine, there was no neurological toxicity or CRS greater than grade 1 in 25 patients who received the new version of the anti-CD19 therapy, known as CD19-BBz(86).

“This is a major improvement,” senior author Siyi Chen, of the USC Norris Comprehensive Cancer Center and a professor in the Keck School of Medicine, said in a statement. “We’ve made a new CAR molecule that’s just as efficient at killing cancer cells, but it works more slowly and with less toxicity.”

CRS occurs when the CAR T cells rapidly proliferate and release a flood of cytokines into a patient’s system, causing a host of reactions from nausea to fever to rash. The USC team adjusted the sequence and shape of the CAR molecules. Modified T cells can still hunt down and kill cancer cells, but with fewer cytokines that are produced more slowly, so the patient’s body can clear them before they build up in the bloodstream. Thus, the treatment produces long lasting benefits without the toxic effects.

“Toxicities are currently the biggest barrier to the use of CAR T-cell therapy,” Chen said. “My hope is that this safer version of CAR T-cell therapy could someday be administered in outpatient settings.”

The adverse events associated with CAR T-cell therapy have been of great concern to CMS, which just finished taking public comment on a proposal that would require Medicare patients receiving the treatment to be enrolled in clinical studies or registries before cancer centers could get reimbursement. Payment would come with strings attached: extensive data reporting duties that would include collection of patient reported outcomes for up to 2 years.

Major cancer centers have said that this requirement could prove untenable; some will not administer the treatment to Medicare patients. Meanwhile, community oncology clinics have asked if the proposal is worded in a way that excludes them. But a less toxic version of CAR T-cell therapy suitable for outpatient administration could make life-saving treatment accessible to a wider range of patients; advocacy groups have cited the need for travel as a barrier to treatment.

The next step for the USC team is to perform a multicenter phase 2 study to test safety and efficacy in a larger group of patients, according to Chen.

Reference

Ying Z, Huang XF, Xiang X, et al. A safe and potent anti-CD19 CAR T cell therapy [published April 22, 2019]. Nature Med. doi: 10.1038/s41591-019-0421-7.

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