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Replies to post #202455 on Biotech Values
Younger patients have a stronger immune system, so it seems reasonable that they would be exposed to a greater risk from CRS.
Sally Church, a Novartis vet with a doctorate from King’s College, writes the highly regarded Biotech Strategy Blog, where she specializes in covering cancer treatments. She’s been following the CAR-T field closely for 4 years, and she was immediately puzzled by Juno’s position.
The chemo fludarabine was used in the study to complete a round of lymphodepletion, eliminating diseased B cells to assist the newly inserted CAR-T cells to repopulate and do their work. It’s the same type of conditioning patients receive for hematopoeitic stem cell transplants. It’s also a procedure used in other CAR-T trials, with no history of cerebral edemas. And there’s no record of fludarabine being linked to cerebral edemas, she writes in her blog. Church gave me access to the article, which you can find here. (Note: There is a pay wall. If you’ve got the budget, we highly recommend you sign up.)
Then she asked a group of hematologists what they knew of a connection. Response: Nothing. And she queried Dr. Stephan Grupp (CHOP), who “probably treated more pediatric ALL patients with CAR T cell therapy than anyone”:
“We have not seen significant cerebral edema in any of our pediatric ALL patients on the CHOP/Penn study treated with CTL019, many of whom received fludarabine. CNS-related side effects have been seen, including confusion, aphasia and seizures in a small number of patients, but these effects have all resolved. Obviously, it is always hard to attribute toxicity to the chemo vs. the CAR T cells when both are given around the same time, but we believe the self-limited CNS side effects we have reported are more likely to be due to the T cells.”
Both Juno as well as rival Kite Pharma use CD-28 as a co-stimulation domain, she adds. Penn/CHOP/Novartis use 4–1BB. There are differences in patient responses, but no cases of cerebral edema have been reported by Kite so far, though Kite has had the same limited CNS issues that Juno has reported.
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