Regulatory authorities worldwide are tightening their monitoring mechanisms and launching their own investigations after reports of secondary malignancies potentially linked to chimeric antigen receptor T cell therapies.
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In November 2023, the FDA announced it was investigating the “serious risk” of malignancies in patients who have been treated with BCMA- or CD19-directed autologous CAR-T cell immunotherapies. The announcement has garnered attention from regulatory authorities and industry leaders in regions including South Korea, the EU and the U.K.
Chimeric antigen receptor (CAR) T cell therapy was developed more than three decades ago by Carl June, an immunologist at the University of Pennsylvania who wanted to circumvent the adverse effects of bone marrow transplants used in treating blood cancers. Today, six CAR T cell therapies—Novartis’ Kymriah, Johnson & Johnson/Janssen’s Carvykti, Bristol Myers Squibb’s Abecma and Breyanzi and Gilead/Kite’s Tecartus and Yescarta—have been approved for various blood cancers and 217 more are in Phase II clinical trials and later stages of development for different cancers.
All six approved therapies are covered under the FDA’s safety investigation.
Tightening Global Regulations
A European Medicines Agency (EMA) representative told BioSpace in an email that “a thorough review of all available evidence is ongoing” by the Pharmacovigilance Risk Assessment Committee (PRAC), an EMA arm that assesses and monitors medicines.
“This includes the 23 cases of various types of T-cell lymphoma or leukemia that were present in EudraVigilance at the time of signal validation,” the representative said, adding that these cases overlap with ones reported to the FDA.
In a statement emailed to BioSpace, Janine Jolly, deputy director of benefit/risk evaluation at the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA), said the regulator is aware that the FDA and the EMA’s PRAC are investigating a signal of serious risk of T-cell malignancy following treatment with BCMA-directed or CD19-directed autologous CAR T cell immunotherapies. She noted that secondary malignancies are considered a potential risk for products in this class. However, she said the MHRA “will consider this issue further and communicate any new advice to healthcare professionals and patients upon completion of our review.”
An FDA representative told BioSpace in an email that while the potential risk of developing secondary malignancies is indeed labeled as a class warning in the U.S. prescribing information for approved CAR T cell immunotherapies, “the FDA’s safety communication describes reports specifically of T-cell malignancy.”
Further east, South Korea announced in December 2023 that it is monitoring the side effects of the two CAR T cell therapies approved in that country, Kymriah and Carvykti.
“The Korean regulatory agencies will now be more focused on receiving expansive data regarding malignancies as well,” said Sasmitha Sahu, a pharma analyst at GlobalData who covers immunology and oncology, in a GlobalData report.
Sahu told BioSpace that South Korea’s Ministry of Food and Drug Safety (MFDS) appears to design its regulatory policies based on FDA guidelines. However, unlike in the U.S. and Europe, where there are observatory units for tracking CAR T cell therapy’s adverse effects, South Korea does not yet have such checkpoints in place because the medicines were recently approved in the country.
“It is not clear what kind of active steps the South Korean agencies have taken, but they have definitely directed hospitals where these CAR T cell therapies are administered to closely track incidents or the appearance of secondary malignancies,” Sahu said. “The mandated monitoring of all the reporting of any suspected adverse reactions, including T-cell malignancies [and] adverse effects, may lead to the creation of a similar dedicated registry for patients who are administered CAR-T therapies.”
The FDA requires 15 years of patient follow-up for all approved CAR-T therapies to monitor their long-term safety profile. Following the reports of T cell malignancies in patients who had previously received CAR-T therapies, the regulator recommended life-long surveillance. “Monitoring [CAR T cells] could slow down the regulatory enthusiasm across all the regions,” Sahu said. “It may prompt the need to do a cautious wait-and-watch approach and may elicit further changes in the regulatory approval process.”
In an email to BioSpace, a representative for Gilead said, “We are confident in the overall benefit-risk profile of both Yescarta and Tecartus, having treated 17,700 patients to date in both clinical trials and the commercial setting. There is no evidence to date that treatment with Yescarta or Tecartus has a causal role in the development of malignancies of T-cell origin.”
In a similar vein, the FDA representative said, “The overall benefits of these products continue to outweigh their potential risks for their approved uses.” A global group of cancer and cell therapy leaders concluded the same in a commentary recently published in Nature, while stressing that more information is needed.
Perception: Pros and Cons
Shriya Das, a biotech professional who managed one of Advenchen Laboratories’ Phase I and II oncology clinical trials in South Korea and Japan, said that while current clinical trials will go ahead as planned, it may take longer to fill them. “Everybody reads newspapers, everybody is aware of what’s happening. Recruitment could slow down because patients and potential participants could get a scare about trying a new investigational treatment.”
Das additionally noted that the therapies will face stronger scrutiny by regulatory authorities moving forward. However, she said, even if the FDA does find concerning evidence, the investigation could provide valuable data and insights for developing more-effective and safer treatments, ultimately leading to better patient outcomes. Another benefit of the FDA’s investigation is that it will build the public’s confidence in regulatory authorities, Das said, as patients will see that medicines are still monitored after approval.
Patience Asanga is a Nigeria-based freelance science journalist who writes about the environment, biotechnology and life sciences.
