While the FDA continues to investigate reported cases of T cell malignancies in patients who received CAR-T therapies, the cause of the secondary cancers remains unclear.
Pictured: Illustration of a pile of question marks, with a yellow question mark on top/iStock, Vladislav Chorniy
We’re all encouraged with the progress that has been made over recent years with regulatory approvals of chimeric antigen receptor (CAR) T cells. The FDA has greenlit CAR-T therapies to treat several types of hematological malignancies, using the body’s own immune system to fight cancer to achieve sustained remissions. In the case of leukemia, two patients have remained cancer-free for a decade after infusion.
The advent of CAR T cells has “been remarkable in the area of oncology,” Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said at the Biotech Showcase earlier this month in San Francisco during JPM Week. However, what if CAR-T therapies caused secondary cancers in the very patients they were designed to save?
It’s a conundrum that regulators and oncologists are confronted with following the November 2023 launch of an FDA probe of malignancies linked to CAR-T therapies. Last week, the agency pushed for a class-wide boxed warning on all commercial CAR-T therapies from manufacturers of licensed BCMA-directed and CD19-directed CAR T cell immunotherapies due to the “risk of T cell malignancies, with serious outcomes, including hospitalization and death.”
So far, the available data show that the development of secondary cancer following CAR T cell therapy is a rare occurrence and a comparatively low-risk cancer treatment, as regulatory authorities worldwide are increasing scrutiny and launching their own investigations.
Writing in an article published Wednesday in The New England Journal of Medicine, CBER’s Marks and Nicole Verdun reported that more than 27,000 CAR-T doses have been administered in the U.S. and that as of the end of December 2023, the FDA is aware of 22 cases of T cell cancers that occurred after treatment.
Marks and Verdun revealed that in three of those cases, genetic sequencing data found the CAR transgene in a malignant clone, suggesting that (emphasis my own) “the CAR-T product was most likely involved in the development of the T-cell cancer.” But the FDA appears to be sending out mixed signals on the issue.
I’m pretty sure I didn’t imagine when Marks, who is also a hematologist oncologist, said at the Biotech Showcase earlier this month that it “does look like there’s a causal relationship” between CAR-T therapy and the secondary cancers. That was based on the same 22 cases.
As I am someone who picks my words carefully for a living, I’m assuming Marks at the FDA does as well—especially on the issue of causality. I don’t think Marks chose the term “causal relationship” by accident. Was the NEJM piece Marks’ attempt to walk back his comment about a causal relationship earlier this month at Biotech Showcase? I’ve asked the FDA for clarity on this point and will let you know if I hear back.
“Like many things at FDA, don’t take what I say today to be the final word because over the coming months as we learn more we will adapt and update our information,” Marks said in a disclaimer at the Biotech Showcase. The CBER chief said that if physicians see new T cell malignancies in patients, they should contact manufacturers and the agency and collect patient samples to test for the presence of the CAR transgene.
Not surprisingly, the FDA has recommended that patients and clinical trial participants who receive CAR-T therapies should be monitored for new malignancies for the rest of their lives. “For now, such cancers appear to be relatively rare adverse events,” Marks and Verdun wrote in the NEJM, while acknowledging that relying solely on post-marketing surveillance could underestimate these secondary cancers. We shall see.
Greg Slabodkin is the News Editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.
