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Understanding the Implications of T-cell Cancers Following CAR-T Therapy

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Dr. Jessica Nelson
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Understanding the Implications of T-cell Cancers Following CAR-T Therapy

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As of December 31, 2023, the US Food and Drug Administration (FDA) has reported 22 cases of T-cell cancers following treatment with Chimeric Antigen Receptor T-cell (CAR-T) products. These occurrences are currently considered rare adverse events. However, they have sparked conversations and necessitated further exploration into the potential implications and risks associated with CAR-T therapy.

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The Safety Profile of CAR-T Therapy

Despite the reported cases of T-cell cancers following CAR-T treatment, the FDA and stakeholders firmly believe that the benefits of CAR-T therapy outweigh these risks. CAR-T therapy has revolutionized the treatment of B-cell malignancies and is currently in its incipient stages for Acute Myeloid Leukemia (AML) treatment. Most notably, the FDA recently lifted the clinical hold on the investigational new drug (IND) application for HEMO-CAR-T, a CAR-T therapy for the treatment of AML. If successful, this therapy could provide a new treatment pathway for patients with AML.

Investigating the Risk of Secondary Cancer

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The FDA is actively investigating the possibility that CAR-T cell therapy may increase the risk of developing a second cancer. A study by researchers from the University of Pennsylvania analyzed 449 patients who received CAR-T cell therapy. They found that 16 (3.6%) had developed a secondary primary malignancy (SPM) after a median follow-up period of 10.3 months. The most frequently observed SPMs were solid cancers, including skin, prostate, and 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. However, it is still unclear if these cases were indeed caused by CAR-T cell therapy, necessitating further investigation by the FDA.

Regulatory Actions and Future Outlook

In light of these findings, the FDA recently required the manufacturers of six licensed BCMA and CD19 directed CAR-T cancer treatments to add boxed warnings to their product labels due to the risk of T-cell malignancies. This decision is based on postmarketing adverse event reports and clinical trial reports. Additionally, the FDA has issued postmarketing requirements for each CAR-T sponsor to conduct long-term observational studies to further evaluate and understand the risk of malignancies associated with their drugs. Such actions underscore the FDA's commitment to patient safety and the ongoing monitoring of potential risks associated with CAR-T therapy.

Ensuring the Long-term Safety of CAR-T Therapy

While the incidence of secondary T-cell lymphomas (TCLs) following CAR-T therapy is less than what is typically observed after checkpoint therapy, it is essential to maintain vigilance. Improved prospective biobanking and comprehensive recording of adverse effects are required to assess risk further. The FDA will continue to gather more information about reported T-cell malignancies and will provide updates as substantive new information becomes available. This ongoing monitoring and analysis will ensure that the safety profile of CAR-T therapy is continually updated, helping patients, physicians, and caregivers make informed decisions about treatment options.

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