Risk of Secondary Cancer Investigated After CAR T-Cell Therapy
The FDA is investigating the potential that CAR T-cell therapy may increase the risk of developing a second cancer.
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The US Food and Drug Administration (FDA) recently announced an investigation into the potential risk that chimeric antigen receptor (CAR) T-cell therapy – an innovative type of cancer immunotherapy – could lead to the development of a second cancer. Now, a study by University of Pennsylvania (UPenn) researchers shows that secondary cancer development is rare after CAR T-cell therapy and that many patients have achieved long-lasting remission.
FDA investigation after CAR T-cell therapy
Chemotherapy, radiotherapy and stem cell transplants are common tools in the oncologist's arsenal to treat cancer. But on rare occasions, these treatments can run the risk of causing new cancers, known as secondary primary malignancies.
What is a secondary primary malignancy?
Secondary primary malignancies (SPMs) are new cancers that occur in people who previously had cancer. Some cancer treatments, such as chemo and radiotherapy, can increase the risks of SPM. These can arise months to years after treatment and are unrelated to the original cancer.
CAR T-cell therapy is a type of personalized cancer treatment. Patients’ T cells are extracted from blood and modified to produce a CAR, which enables them to target and kill cancer cells. The modified cells are cultured in huge numbers and then readministered to the patient.
The first CAR T-cell therapy was approved in 2017 and, despite the potential for serious side effects such as cytokine release syndrome, many patients from early clinical trials have achieved long-lasting remission.
Currently, CAR T-cell therapy is approved only to treat blood cancer patients who have already undergone previous therapies and have either relapsed or no longer respond to treatment.
However, in 2023 the FDA announced it would investigate the occurrence of T-cell malignancies (TCMs) in patients who had previously received CAR T-cell therapy. This comes after reports of several secondary TCMs, including a CAR-positive lymphoma.
The FDA states that, although these treatments can provide huge benefits to patients that outweigh potential risks, it will continue to monitor the situation in case of the need for regulatory action and investigate the risks of SPMs.
This investigation prompted UPenn researchers, led by Dr. Marco Ruella, to analyze the occurrence of secondary cancers in patients treated with commercial CAR T-cell therapy at UPenn. The report is published in Nature Medicine.
“Low incidence” of secondary T-cell lymphomas
The researchers began by analyzing the case of a patient with a CAR-positive T-cell lymphoma – concluding that the detection of the modified CAR gene was likely due to the presence of CAR T cells in the sample, rather than the lymphoma cells harboring the modified gene themselves.
“When this case was identified, we did a detailed analysis and concluded the T-cell lymphoma was not related to the CAR T-cell therapy,” Ruella explained in a press release. “As the news of other cases came to light, we knew we should go deeper, to comb through our own data to better understand and help define the risk of any type of secondary cancer in patients who have received CAR T-cell products.”
Of the 449 patients analyzed who received CAR T-cell therapy at UPenn, 16 (3.6%) had developed an SPM after a median follow-up period of 10.3 months.
The most frequently observed SPMs were solid cancers. This included six skin cancers, three prostate cancers and three non-small cell lung cancers.
The researchers estimated that the 5-year incidence of SPM is 15.2% for solid cancers and 2.3% for blood cancers.
“What we found was very encouraging and reinforces the overall safety profile for this type of personalized cell therapy,” he added.
Further investigation needed
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.
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