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Cell Therapy Research Consortia Responds to FDA's CAR T-Cell Therapy Warning

NEW YORK – The International Society for Cell and Gene Therapy (ISCT) on Tuesday published a commentary in Nature Medicine in response to the US Food and Drug Administration's announcement that it would investigate the risk of T-cell malignancy in patients treated with BCMA- or CD19-directed autologous CAR T-cell immunotherapy.

In November 2023, the FDA said it had received reports of such malignancies from clinical trials and post-marketing adverse event data sources linked to Bristol Myers Squibb's Abecma (idecabtagene vicleucel) and Breyanzi (lisocabtagene maraleucel), Janssen's Carvykti (ciltacabtagene autoleucel), Novartis' Kymriah (tisagenlecleucel), and Gilead Science's Tecartus (brexucabtagene autoleucel) and Yescarta (axicabtagene ciloleucel).

While supporting the FDA's call for investigation into the malignancies, the ISCT also said that the benefits of CAR T-cell therapies still outweigh the potential risks and recommends that commercial CAR T-cell therapies remain available to patients. The ISCT joined with the American Society for Transplantation and Cellular Therapy, the European Society for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research (CIBMTR), and the Parker Institute for Cancer Immunotherapy in authoring the commentary.

In the paper, the ISCT authors noted that the FDA had flagged 20 cases of T-cell malignancies associated with the therapies, while manufacturers report that more than 34,400 patients have been treated. In data from the CIBMTR, 565 secondary or subsequent malignant neoplasms were reported in 485 of 11,345 patients who received commercial CAR T-cell therapy at a median follow-up time of 13 months. In a subgroup of 8,060 patients who were enrolled in post-authorization safety studies, the researchers found 420 malignancies in 357 patients. However, as of December 2023, only three reported T-cell malignancies were among these cases, and none showed aberrant expression of CD19 in the tumor cells.

"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 authors wrote, adding that T-cell malignancies have also been observed with other treatments such as immune checkpoint blockade.

"The fundamental question from [the FDA's report] is whether or not there is a causal link between CAR T therapy and these rare T-cell malignancy cases and in how many patients," Bruce Levine, past president of ISCT and lead author on the publication. "Currently, there are too many unknown factors related to the 20 reported cases, making it premature to establish the magnitude of what appears to be a very low risk."

The ISCT said the risks should be put into perspective in comparison to treatments such as chemotherapy and radiation therapy, which carry substantial risks including genotoxicity and a predisposition to secondary cancers at a higher rate than what is suggested by the reported T-cell malignancy cases following CAR T-cell therapy.