The novel kind of cancer immunotherapy known as chimeric antigen receptor (CAR) T-cell treatment has prompted the US Food and Drug Administration (FDA) to announce an investigation into the potential risk that it could cause a second cancer to emerge. Researchers from the University of Pennsylvania (UPenn) (USA) have now demonstrated that many patients have experienced long-lasting remission and that the development of secondary malignancy is uncommon following CAR T-cell therapy. Rarely, side effects from stem cell transplants, radiation therapy, and chemotherapy can include the possibility of developing new malignancies, or secondary primary malignancies. SPMs, or secondary primary malignancies, are newly diagnosed tumors in individuals with a history of malignancy. Certain cancer therapies, like radiation and chemotherapy, can make SPM more likely. These cancers have nothing to do with the initial disease and may arise months or years after treatment. Despite the potential of serious side effects including cytokine release syndrome, the first CAR T-cell therapy was approved in 2017, and several patients from early clinical studies were able to achieve long-lasting remission. Only patients with blood cancer who have already had prior therapies and have either relapsed or are no longer responding to treatment are eligible to receive CAR T-cell therapy at this time. But the FDA declared in 2023 that it will look at T-cell malignancies (TCMs) in individuals who had previously had CAR T-cell therapy. This follows the discovery of multiple secondary TCMs, one of which was a CAR-positive lymphoma. According to the FDA, despite the fact that these medicines can have far greater advantages for patients than potential risks, it will keep monitoring the situation in case regulatory action is required and look at the potential risks associated with SPMs.
Researchers at UPenn examined the incidence of recurrent malignancies in patients receiving commercial CAR T-cell treatment as a result of this inquiry. The report is published in Nature Medicine. After reviewing the case of a patient with a CAR-positive T-cell lymphoma, the researchers came to the conclusion that the presence of CAR T cells in the sample, rather than the lymphoma cells expressing the changed gene, was most likely the reason the modified CAR gene was detected. 16 (3.6%) of the 449 patients at UPenn who had CAR T-cell treatment were found to have acquired an SPM following a median follow-up of 10.3 months. Solid tumors accounted for the majority of SPMs that were observed. This comprised three prostate tumors, three non-small cell lung cancers, and six skin cancers. The researchers estimated that the 5-year incidence of SPM is 15.2% for solid cancers and 2.3% for blood cancers. Importantly, these therapies’ initial approval came with requirements to conduct longer-term follow-up studies over a 15-year period to assess the potential risks of treatments long-term. Safety warnings on drug labels are now mandated by the FDA for these products. Nonetheless, further research and investigation by the FDA are required to determine if these cases were indeed caused by CAR T-cell therapy. The 5-year incidence of SPM, according to the researchers’ estimates, is 2.3% for blood malignancies and 15.2% for solid tumors. Significantly, in order to evaluate the possible long-term dangers of these medicines, longer-term follow-up studies over a 15-year period were necessary for the original approval of these medications. The FDA has now required these products to have safety warnings on their drug labels. However, more study and an examination by the FDA are necessary to ascertain whether CAR T-cell therapy was the actual cause of these cases.
Reference: Ghilardi G, Fraietta JA, Gerson JN, et al. T-cell lymphoma and secondary primary malignancy risk after commercial CAR T-cell therapy. Nat Med. 2024:1-1. doi: 10.1038/s41591-024-02826-w