Secondary Cancers after Chimeric Antigen Receptor T-Cell Therapy
Nicole Verdun, Peter Marks
N Engl J Med January 24, 2024
DOI: 10.1056/NEJMp2400209
Since the first such product was approved in 2017, chimeric antigen receptor (CAR) T-cell therapies have become important treatments for relapsed or refractory hematologic cancers, and the six products involving autologous CAR T cells that have been approved in the United States now cover a range of indications spanning relapsed or refractory B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin’s lymphomas, and multiple myeloma (see table). In addition, 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 hematologic cancers and to target solid tumors. CAR T cells are also under investigation for the treatment of nonmalignant conditions, such as autoimmune diseases.1
The demonstrated efficacy of the current generation of approved CAR-T products comes along with several well-described safety concerns that are noted in the products’ labeling, including risks of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, various forms of cytopenia, and hypogammaglobulinemia. Better understanding of some of these risks has led to improved outcomes, such as for patients who develop cytokine release syndrome.2
All currently approved CAR-T products employ T cells that are produced by using viral transduction to transfer the genetic construct. Given the relatively recent deployment of these therapies, the Food and Drug Administration (FDA) has issued draft guidance recommending that people who receive CAR T cells engineered with integrating vectors be monitored for extended periods for adverse events, including cancers.3 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. For instance, the lentiviral vector constructs, despite integrating in a semirandom fashion into the genome, have affinity for areas of the genome in which active gene expression is taking place, which may pose a risk for insertional oncogenesis.4
As of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR-T products. 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. Cases have been reported in conjunction with five of the six available CAR-T products, but the small number of cases and variation in product use preclude conclusions about the strength of an association with any specific product. Some of these cases are still under investigation.
In three 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. With more than 27,000 doses of the six approved products having been administered in the United States, 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. But 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, but in many instances, adequate samples of the lymphomas have not been retained for testing by means of polymerase chain reaction or genome sequencing. Determination of whether the T-cell cancer is associated with the CAR construct therefore most likely won’t be possible for every case reported to date. The FDA plans to provide updates as substantive new information becomes available.
It is important for clinicians caring for people who have received CAR T cells to report the occurrence of any new cancer. At this time, we recommend that patients and clinical trial participants who receive treatment with these products be monitored for new cancers throughout their lives, since — owing to the relatively recent widespread introduction of CAR-T products into clinical care — we don’t yet know 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 by contacting us at 1-800-FDA-1088 or visiting the website for our medical product safety reporting program (http://www.fda.gov/medwatch. opens in new tab).
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.5 Comprehensive tumor-testing strategies might also generate information on the risk for and nature of these cancers and provide additional mechanistic insights. For now, secondary T-cell cancers occurring after the use of CAR T cells for the treatment of relapsed or refractory hematologic cancers appear to be relatively rare adverse events. Appropriate product labeling will be a resource that can help clinicians manage conversations with patients about the benefits and risks associated with treatment options.
