The New England Journal of MedicineSecondary Cancers after Chimeric Antigen Receptor T-Cell Therapy

Advancing CAR T-cell Therapies: Efficacy, Safety, and Emerging Concerns in Hematologic Cancers

Since the approval of the first CAR T-cell therapy in 2017, these innovative treatments have marked a significant advance in the fight against hematologic cancers, offering hope for patients with relapsed or refractory conditions. As the number of approved autologous CAR T-cell products grows, and with numerous others in development, the focus has expanded to enhancing their efficacy and safety profile, and extending their application beyond hematologic malignancies to include autoimmune diseases and potentially solid tumors. However, alongside their therapeutic benefits, CAR T-cell therapies have been associated with serious safety concerns and emerging reports of secondary T-cell cancers post-treatment, prompting calls for vigilant monitoring and further research.

Key Points:

• CAR T-cell therapies have been approved for various hematologic cancers, including B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin’s lymphomas, and multiple myeloma, demonstrating significant efficacy.
• Safety concerns associated with CAR T-cell therapies include cytokine release syndrome, neurotoxicity, cytopenia, and hypogammaglobulinemia, with improved management strategies for some conditions like cytokine release syndrome.
• All approved CAR-T products use viral transduction for genetic construct transfer, leading the FDA to recommend long-term monitoring for potential adverse events, including secondary cancers.
• As of December 31, 2023, the FDA had noted 22 cases of T-cell cancers post-CAR T-cell therapy treatment, with some cases showing the CAR transgene in the malignant clone, indicating a potential link to the therapy.
• Despite the low overall rate of T-cell cancers among recipients, given the more than 27,000 doses administered, there’s an emphasis on the necessity of postmarketing surveillance to capture all potential cases.
• The FDA encourages clinicians to report new cancer occurrences in patients treated with CAR T-cell therapies and has issued guidance on sample collection for testing the presence of the CAR transgene.
• Future strategies may include targeted insertion of the CAR construct and comprehensive tumor-testing to minimize cancer risks associated with CAR T-cell therapies.
• The occurrence of secondary T-cell cancers post-CAR T-cell therapy remains relatively rare, but it necessitates continued vigilance and research to understand and mitigate risks.

A study published in Nature Medicine found that CAR T-cell therapy not only shows promise in treating cancer but also in potentially treating autoimmune diseases, showcasing the versatility of this therapeutic strategy.

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