Until the end of 2023, there were 22 cases of secondary T-cell cancers reported to US Food and Drug Administration (FDA) that occurred after treatment with CAR-T products for relapsed or refractory haematologic malignacies. Such cancers have included T-cell lymphoma, T-cell large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. Among the 14 cases for which adequate data are currently available, the cancers have manifested within 2 years after administration of CAR T-cells (range, 1 to 19 months), with roughly half occurring within the first year after administration.
In 3 cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer. However, determination of whether the T-cell cancer is associated with the CAR construct most likely won’t be possible for every case reported to date according to Drs. Nicole Verdun and Peter Marks from the FDA’s Center for Biologics Evaluation and Research in Silver Spring, MD, US, who reported the findings on 24 January 2024 in the NEJM.
The authors wrote that efficacy of the current generation of approved CAR-T products comes along with several safety concerns that are noted in the products’ labelling, including risks of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, various forms of cytopenia, and hypogammaglobulinemia.
Since the first such product was approved in 2017, CAR T-cell therapies have become important treatments for relapsed or refractory haematologic malignancies. Currently 6 products involving autologous CAR T-cells are approved in the US for a range of indications spanning relapsed or refractory B-cell acute lymphoblastic leukaemia, B-cell non-Hodgkin’s lymphomas, and multiple myeloma.
Although CAR-T products have to date been associated with fewer cancers than products made with the previous generation of viruses used for gene therapy transduction, the potential for oncogenesis caused by genomic integration or other mechanisms still exists with the current generation of retroviral vectors.
With more than 27,000 doses of the 6 approved products having been administered in the US, the overall rate of T-cell cancers among people receiving CAR-T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment. However, relying on postmarketing reporting may lead to underestimates of such cases. The FDA is attempting to gather as much information as possible on each of the reported cases. In many instances, adequate samples of the lymphomas have not been retained for testing by means of polymerase chain reaction or genome sequencing.
FDA recommends that patients and clinical trial participants who receive treatment with these products be monitored for new cancers throughout their lives, since it is unknow how long after treatment people remain at risk for these adverse events. If a new cancer occurs after treatment with one of these products, clinicians should contact the manufacturer to report the event and obtain instructions on the collection of patient samples for testing for the presence of the CAR transgene. Clinicians are also encouraged to report such T-cell cancers to the FDA’s MedWatch.
Numerous autologous and allogeneic CAR-T products are in development. Manufacturers of these next-generation products are seeking to improve on the efficacy and safety profile of existing therapies for haematologic malignancies and to target solid tumours. CAR T-cells are also under investigation for the treatment of nonmalignant conditions, such as autoimmune diseases.
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. Comprehensive tumour testing strategies might also generate information on the risk for and nature of these cancers and provide additional insights.
Reference
Verdun N, Marks P. Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy. NEJM; Published online 24 January 2024. DOI: 10.1056/NEJMp2400209