In November 2023, the U.S. Food and Drug Administration (FDA) announced an investigation into chimeric antigen receptor (CAR) T-cell therapies, questioning if these promising cancer treatments were causing new malignancies. This revelation sent shockwaves through the medical community. Bruce Levine, an immunologist and leader in CAR-T therapy, was caught off guard by the news. “Better get smart about it quick,” he thought when a reporter asked for his response to the news.
As of March 2024, the FDA has recorded 33 cases of immune-cell cancers, specifically lymphomas, developing in patients treated with CAR-T cells out of roughly 30,000 treated individuals. This prompted the agency to mandate a warning label on all CAR-T therapies. Yet, many questions remain unanswered.
Chasing the Unknown
Researchers are working to determine if CAR-T therapies are directly causing these secondary cancers. The risk appears rare but must be understood to improve and expand CAR-T use. Initially reserved for last-resort cases, CAR-T treatments are now approved for earlier-stage lymphoma and multiple myeloma. Some companies aim to extend this technology to treat solid tumors, autoimmune diseases, aging and HIV.
Aric Hall, a hematologist at the University of Wisconsin–Madison, noted that, although the technology has received much attention, it is still relatively novel. “I used to joke that for the first ten years, there were more review articles about CAR-T than there were patients who had been treated by CAR-T products.” He warns that rare risks could become significant as the therapy expands to less critically ill patients.
The Challenge of Vector Safety
The risk of malignancy arises from the genetic engineering involved in CAR-T therapy. This process uses retroviruses to insert genetic information into T cells. These modified cells, designed to target and kill cancer cells, might inadvertently activate cancer-promoting genes or deactivate tumor-suppressing ones.
This risk, known as insertional mutagenesis, has historical precedent. About 20 years ago, gene therapies for severe combined immunodeficiency syndrome caused leukemia in some treated infants. To mitigate such risks, scientists have refined the vectors used in CAR-T therapy, making them safer. The FDA recommends testing CAR-T products to demonstrate that the vectors cannot replicate.
The Search for Evidence
The FDA’s warning prompted further scrutiny. Levine and colleagues published a commentary urging a deeper examination of the data. In January, the FDA reported that the agency was aware of 22 cases of leukemia among CAR-T recipients, with 11 further case notifications received since then, according to reporting in Nature. Some cases contain the CAR gene, suggesting a possible causal link. However, proving causality is complex.
In one case, a 51-year-old man treated for multiple myeloma developed T-cell lymphoma. The cancerous cells carried the CAR gene, but he also had genetic predispositions to cancer, complicating the attribution solely to CAR-T therapy. Researchers at the Peter MacCallum Cancer Center in Melbourne, Australia, are investigating whether pre-cancerous cells existed before the CAR-T treatment.
Rare but Real Risks
Despite the concerns, secondary cancers linked to CAR-T therapy appear rare. At the University of Pennsylvania, only 3.6% of 449 CAR-T-treated patients developed secondary cancers, mainly unrelated to the therapy. At the Mayo Clinic, researchers found similar rates of T-cell lymphoma in CAR-T-treated and untreated cancer patients.
Following the FDA’s warning, Hall began informing patients of the potential risk, emphasizing its rarity compared to the immediate threat of their existing cancer. Crystal Mackall, a pediatric oncologist at Stanford University, concurs, stating, “Most cancer therapies can cause cancer. This is one of the paradoxes of our business.”
Expanding Possibilities and Vigilance
Researchers are exploring CAR-T for other conditions, including solid tumors, autoimmune diseases, aging and HIV. Early trials show promise, but long-term risks must be monitored. For severe conditions like lupus, CAR-T therapy’s benefits might outweigh the potential risks. Researchers will continue investigating novel CAR-T applications while remaining vigilant to ensure patient safety.
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