Could an old Amgen-developed RA drug make CAR-T treatments safer?

The personalized CAR-T cells that are FDA-approved to treat blood cancers, Gilead’s Yescarta and Novartis’s Kymriah, can raise the risk of a side effect that has been challenging to prevent and treat: cytokine release syndrome (CRS).

The frightening collection of symptoms CRS can cause range from rash and fever to severe neurological problems. Oncologists who administer CAR-T treatments often use the immune-suppressing drug Actemra (tocilizumab) to reverse CRS, but it doesn’t always shut down all the symptoms.

Two new studies provide some insight into why that is—and how a different drug might improve the treatment of CRS, or better, prevent the CAR-T side effect altogether.

Actemra, a Genentech drug first approved by the FDA in 2010 to treat rheumatoid arthritis, works by blocking interleukin-6 (IL-6), an inflammatory cytokine that’s present in abnormally high levels in patients with the disease. The FDA approved the drug last year to treat CRS in patients undergoing CAR-T therapies.

But IL-6 isn’t the only cytokine that regulates CRS, researchers at San Raffaele Hospital in Italy discovered. They studied mouse models of leukemia with induced CRS and discovered that high levels of the inflammatory cytokine IL-1 appeared hours before IL-6 did.

Furthermore, IL-1 seemed to spur production of IL-6. The study (PDF), published in the journal Nature Medicine, was coauthored by Attilio Bondanza, a former scientist at San Raffaele Hospital who is now CAR-T clinical program leader at Novartis Institutes for BioMedical Research (NIBR).

Bondanza and his colleagues discovered that if they gave the mice a different RA treatment, Kineret (anakinra), prior to administering CAR-T cells, they could significantly improve overall survival.

Kineret, which was originally developed by Amgen and approved in 2001, differs from Actemra in that it is a small protein that can penetrate the brain, potentially limiting neurological side effects of CRS. Kineret is now marketed by Sweden-based Sobi.

"In neurotoxicity, there is no advantage to giving an IL-6 inhibitor because it does not cross the blood-brain barrier," Bondanza explained in an interview with The Scientist.

Another new study helped explain the role of IL-1 in CRS. A team of researchers at Memorial Sloan Kettering in New York discovered that existing immune cells in mice produce most of the dangerous molecules involved in CRS.

They observed that IL-6, IL-1 and nitric oxide mediate CRS and that treating the mice with Kineret was a more effective way to stop the side effect than shutting down IL-6. They also published their results (PDF) in Nature Medicine.

Cancer researcher and coauthor Michel Sadelain told The Scientist his group hopes that clinical trials will help determine whether blocking IL-1 in patients can prevent CRS. In the Nature Medicine paper, the team suggested that their results could also be used to design a CAR-T treatment that has IL-1 blockage built into it.

As for Bondanza, he will be bringing his CRS expertise to Novartis, where NIBR has tagged cell and gene therapy as one of its 6 therapeutic priorities. At the BIO International Convention in Boston this week, NIBR’s president, Jay Bradner, outlined several of the unit’s oncology efforts, including Project Drive, an effort to map cancer-causing genes, and its partnership with Intellia Therapeutics to use the gene editing system CRISPR/Cas-9 to make CAR-T cells.

NIBR’s overarching goal is to bring in researchers with innovative ideas and give them the resources to rapidly transform new technologies into usable therapies. "We have 6,000 scientists and they should feel empowered and enabled to work alongside, shoulder-to-shoulder, with the innovator that can advance their idea," Bradner said during the BIO conference.

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