The FDA Investigates T-Cell Malignancies in CAR-T Therapy

The unforeseen ascent and success of CAR-T therapy surprised many people in the industry (including Carl June, who explains in this interview that no one could have predicted the success of CAR T). But have some elements of risk been missed? The FDA has now launched an investigation into T-cell malignancies among patients treated with BCMA- or CD19-directed autologous CAR T cell immunotherapies. 

In a recent statement, the FDA specified that the cancer risk applies to all currently approved BCMA-directed and CD19-directed genetically modified autologous CAR T cell immunotherapies. Incidences of T-cell malignancies have been documented across various products in this therapeutic class, including Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta.

“Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes, including hospitalizations and death, and is evaluating the need for regulatory action,” says the statement. 

The FDA also highlighted that the risk of secondary malignancies is already included as a “class warning” in the US prescribing information for these CAR-T therapies. The investigation, however, will specifically delve into reports related to T-cell malignancy.

“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” said the FDA. “In the event that a new malignancy occurs following treatment with these products, contact the manufacturer to report the event and obtain instructions on collection of patient samples for testing.”

The majority of reports were accumulated from clinical trials and postmarketing adverse event data surveillance. 

The response…
 

Despite the documented side effects associated with CAR-T therapy, the relatively recent introduction of this treatment approach has resulted in an insufficiently defined understanding of the underlying pathobiology – at least, according to the concerns raised by the FDA. Even so, T cell cancers have seldom been linked to treatment in previous instances.

On the social media platform X, Bruce Levine, Professor in Cancer Gene Therapy at Penn Medicine questioned “the clinical status of the patients in terms of immunosuppression, prior therapy, conditioning chemotherapy, evidence of prior clonal hematopoiesis.” He also wondered whether integration site analysis was performed, and whether there were undetected/unknown early warning signs, among other questions. 

Levine concluded: “It’s important to put into context the remote though real risk when compared to conventional chemotherapy that has significant long and short term side effects, including genotoxicity and predisposition to secondary cancers.”

Maksim Mamonkin – a CAR-T expert at Baylor College of Medicine’s Center for Cell and Gene Therapy – followed a similar line of enquiry to Levine after suggesting secondary cancers are “definitely not something that we routinely see or something that we expect,” in conversation with Reuters.

Adding to the confusion, John DiPersio, Director of the Center for Genetic and Cellular Immunotherapy at Washington University School of Medicine in St. Louis, said his center had treated up to 700 patients in conversation with The New York Times. Though no treatment is risk-free, DiPersio stated that he hadn’t seen a single patient develop a new T cell cancer. For him, patients “are all going to die, and they are all going to die quickly without this treatment. It saves their life. It works in a substantial portion of patients. The benefit is enormous.”

Companies are also feeling the pinch of this investigation. According to Reuters, Novartis has released a statement saying that Kymriah has been used in more than 10,000 patients. “[...] there is no evidence to date that would change our confidence in Kymriah’s benefit/risk profile,” Novartis stated. “As part of our continuous safety monitoring, Novartis has not identified a causal relationship between Kymriah and secondary malignancies. We are fully committed to patient safety and will continue to work with the U.S. Food and Drug Administration.”

A representative for Bristol Myers Squibb, which manufactures two approved CAR-T cell therapies, Abecma and Breyanzi, said “BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary malignancies,” according to Wired. The company reportedly added that more than 4,700 patients have received these therapies either in research trials or as commercial products.

The investigation’s impact on CAR-T therapy remains uncertain. In the meantime, there appears to be a unanimous sense of confusion – or even frustration – among researchers and pharmaceutical companies, who point to a lack of transparency from the FDA. Moving forward, the FDA said it was “evaluating the need for regulatory action.”