Amid high-profile CAR-T safety probe, FDA’s Peter Marks offers first glimpse at data under review

Three months after launching an investigation into the risk of patients developing secondary T-cell cancers after receiving a CAR-T drug, the FDA has shared more information on the cases it has seen so far.

As of the end of 2023, the FDA noticed 22 cases of T-cell cancers following treatment with a CAR-T product, and about a third of them remain under investigation. CAR insertion, which indicates a possible contribution from the CAR-T therapy, was detected in the malignant clone in each of the three cases for which genetic sequencing was performed.

Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER) and Nicole Verdun, M.D., who leads the office of therapeutic products at CBER, shared the latest information in an article published in the New England Journal of Medicine.

The dispatch offers the first official glimpse at the evidence under review at the FDA since the agency announced its CAR-T safety probe in November. But the officials did not share the level of seriousness for the 14 cases that have been adequately investigated.

Previously, the FDA has characterized the outcomes of the secondary cancers as “serious,” including cases of hospitalization and death.

The secondary cancer cases have been reported for five of the six commercial CAR-T products. The one that didn’t have a report linked to it appears to be Gilead Sciences’ Tecartus, according to a label update demand from the FDA.

The FDA is pushing for slightly different warning language for the other five CAR-Ts, and the agency has said it considers the T-cell malignancy risk a classwide problem.

“[T]he small number of cases and variation in product use preclude conclusions about the strength of an association with any specific product,” Marks and Verdun wrote in the article.

While currently available CAR-T products are already an improvement from the first generation of cell therapies, the risk of the emergence of a new cancer—caused by genomic integration from the viral vectors that are used to deliver the CAR-T cells—still exists, Marks and Verdun wrote.

The two FDA officials acknowledged that the rate of T-cell cancers among CAR-T takers “appears to be quite low, even if all reported cases are assumed to be related to treatment.” But they cautioned that the FDA’s current information may not be comprehensive, which could lead to underestimates of the exact scope of the risk.

For the 14 cases on which the FDA has enough information, the cancers manifested between 1 month to 19 months after the administration of CAR-T cells, with about half occurring within the first year. Still, the FDA has revised its patient monitoring recommendations for CAR-T products and now asks recipients to be followed for new cancers throughout their lives, since “we don’t yet know how long after treatment people remain at risk for these adverse events,” Marks and Verdun wrote.

With the new safety signal, the FDA is pushing for a classwide boxed warning outlining the risk of T-cell malignancies on the label of all six existing BCMA- and CD19-directed CAR-T drugs. Besides Tecartus, Gilead’s Yescarta, Bristol Myers Squibb’s Breyanzi and Abecma, Johnson & Johnson and Legend Biotech’s Carvykti, and Novartis’ Kymriah each face increased scrutiny.

One key question that Marks and Verdun didn’t address in their article is why the FDA is specifically applying the perceived risk of T-cell malignancies to autologous CAR-Ts without touching on allogeneic, or “off-the-shelf” candidates, which also use the viral vectors.

The FDA is generally empirical in its decision-making, and “one would have to assume that they saw evidence of T-cell malignancies […] at least in a way that strongly suggested that the manufacturing process used for autologous T-cell therapies would predispose patients to T-cell malignancies,” Zachary Roberts, M.D., Ph.D., chief medical officer at Allogene Therapeutics, said in an interview with Fierce Pharma.

So far, Roberts said he’s not aware of any T-cell malignancy cases from allogeneic cell therapies. As the company’s name suggests, Allogene Therapeutics is focused on allogeneic CAR-Ts.

Autologous and allogeneic products are mechanistically different, Roberts explained. Allogeneic cells don’t persist as long in the body and are typically gone three to six months after treatment. So even if there was a transformed cell administered during the process, it would likely be rejected by the host immune system.

In addition, autologous CAR-Ts are tailor-made for each individual and are typically rushed to the patient for administration. By comparison, allogeneic cells are premade and stored. This gives the drug manufacturer the opportunity to pre-screen the products for insertion site analysis and potentially quarantine a batch with a concerning outgrowth, Roberts said.

In their article, Marks and Verdun acknowledged they don’t have all the information about the T-cell malignancies. But they argued that further improvement of the CAR construct is the right way to go.

“Moving forward, particularly as the use of CAR T cells for indications outside hematology and oncology is considered, new strategies involving targeting insertion of the CAR construct to specific loci might help reduce the risk of cancers due to integration of the CAR construct at oncogenic loci within the genome," the authors wrote.