Cell therapy bigwigs endorse CAR-T in Nature Medicine article amid FDA safety probe

As an FDA investigation into patients developing secondary T-cell cancers rocked the CAR-T world, a group of cell therapy experts, including CAR-T pioneers Bruce Levine, Ph.D., and Carl June, M.D., are lending their support to the emerging immunotherapy in a commentary published in Nature Medicine.

Despite reports of post-treatment secondary malignancies, “the benefits of CAR-T therapies continue to outweigh the potential risks in the vast majority of cases,” the experts wrote in the article, with Levine from Penn Medicine serving as first author.

As the FDA probe continues, treatment centers “should continue to make commercial CAR-T products available to patients when this appears to be the best option possible (based on the most up-to-date and confirmed safety information),” the authors wrote.

Miguel-Angel Perales, M.D., from Memorial Sloan Kettering Cancer Center and current president of the American Society for Transplantation and Cellular Therapy, and Anna Sureda, president of the European Society for Bone Marrow Transplantation, are also listed among the authors.

The FDA announced the probe in November after receiving reports of T-cell malignancies in patients who had taken marketed CAR-T therapies from clinical trials and the FDA Adverse Event Reporting System (FAERS). The agency said it has determined that the risk is applicable to all six approved products, including the first CAR-T, Novartis’ Kymriah, which June and Levine co-invented. The other five are Gilead Sciences’ Yescarta and Tecartus, Bristol Myers Squibb’s Breyanzi and Abecma, plus Johnson & Johnson and Legend Biotech’s Carvykti.

Bruce Levine, Ph.D. (University of Pennsylvania)

“Our goal was to point out what is known and what is unknown,” Levine said in an email with Fierce Pharma.

The researchers spotted 20 reports of T-cell malignancy among about 8,000 adverse events following CAR-T treatments in FAERS. Reporting to the FDA database is not mandatory, and the cases are self-reported by doctors and are therefore not verified by third parties.

“Given that an estimated 34,400 patients have received commercially available CAR-T cells so far, the rate of T-cell malignancies observed is far lower than that seen with some other treatments,” the researchers said.

The team pointed to a 2020 Journal for ImmunoTherapy of Cancer paper, which searched FAERS for T-cell malignancies following treatment of Bristol’s PD-1 inhibitor Opdivo and CTLA-4 agent Yervoy and Merck’s PD-1 drug Keytruda. The rate of T-cell malignancies among those immune checkpoint inhibitors appeared to be lower than that of the CAR-Ts. The study only found 12 cases of T-cell neoplasm out of 50,445 adverse events reported for those three agents in FAERS between 2012 and 2018.

Besides the FAERS system, the Center for International Blood and Marrow Transplant Research (CIBMTR) maintains a database of adverse events from CAR-Ts under the FDA-mandated safety monitoring framework known as Risk Evaluation Mitigation Strategy, or REMS. In CIBMTR, 485 patients were reported to have developed secondary malignant neoplasms—including three T-cell malignancies—among 11,345 recipients of commercial CAR-T products, according to the researchers. That translates into an overall secondary cancer rate of 4.3%.

To put that into context, hematopoietic stem cell transplant, which is a standard of care for several blood cancers, is also linked to increased risks of secondary cancers. Such risk for stem cell transplant is estimated at around 8% to 29%, although the majority of these cases are myeloid-derived, not T-cell-related, the researchers pointed out.

However, because both FAERS and CIBMTR reporting is voluntary, “there is neither a reliable numerator nor a denominator to assess,” the researchers cautioned about their CAR-T analyses.

“We don’t know who the patients are who have been reported to FAERS and how they differ from the patients who have not been reported,” Levine said.

The possibility of the viral vectors used to deliver CAR-T cells inserting themselves into the human genome is a major concern for inducing secondary cancer. Therefore, secondary cancer is a class warning on the labels of FDA-approved CAR-Ts.

It remains unclear whether the 20 FAERS cases were caused by CAR-T treatment. Clinicians recently reported one CAR-positive T-cell lymphoma case five months after getting J&J/Legend’s BCMA-targeted Carvykti. That team of researchers suspected the secondary cancer was potentially driven by genetic mutations that may have existed before Carvykti production although a contribution from the CAR insertion cannot be ruled out.

If all those 20 cases in FAERS were CAR-positive upon thorough investigation, “there would [be] a high level of concern,” Levine said. However, given that CAR-Ts are currently mostly given to patients who had few if any treatment options that were very likely to die of their disease, “this still seems like a small reasonable risk,” he said.

The FDA, in announcing the safety investigation in November, also said the overall benefits of the CAR-Ts still outweigh their potential risks for their approved uses. But industry watchers are concerned over a shift in that benefit-risk calculation as CAR-Ts try to move into earlier treatment settings, where other effective treatment options are available and where a large part of the therapies’ commercial potential lies.

The new Nature Medicine commentary didn’t touch on that earlier-line topic. Levine noted that when advocating for the favorable benefit-risk profile of CAR-Ts, the team used the term “vast majority of cases” in the context of FDA-approved indications.

“Our commentary is also an effort to emphasize the importance and encourage reporting to the voluntary databases, and to encourage transparency and thorough investigations,” Levine said.