Article Impact Level: HIGH Data Quality: STRONG Summary of EMBO Molecular Medicine. https://doi.org/10.1038/s44321-024-00183-2 Dr. Philipp Berg et al.
Points
- CAR T-cell therapy for blood cancers has been linked to isolated cases of secondary T-cell malignancies, raising concerns about long-term safety.
- Multifactorial risks, incomplete post-marketing data, and a lack of molecular testing on tumor samples present challenges in assessing causality.
- Molecular analysis, including vector integration sites and oncogenic potential, is crucial for understanding the mechanisms behind secondary malignancies and ensuring accurate evaluations.
- The study advocates for developing modified causality assessment criteria incorporating molecular methods specific to gene therapy products and their unique characteristics.
- Enhanced assessment frameworks aim to evaluate better and minimize risks associated with CAR T-cell therapy, ensuring its therapeutic benefits outweigh potential long-term complications.
Summary
This study explores the growing concern of secondary T-cell malignancies as potential adverse reactions following chimeric antigen receptor T-cell (CAR T) therapy, particularly for blood cancers. The incidence of such malignancies presents a unique challenge for pharmacovigilance due to the multifactorial nature of the risks involved, including patient-specific factors and incomplete data from post-marketing reports. The analysis, conducted by experts at the Paul-Ehrlich-Institut and University Hospital Cologne, highlights the complexities of causality assessment in these cases and emphasizes the importance of molecular testing for accurate evaluations. Testing for vector presence, integration sites, and gene expression profiles is necessary to understand contributing factors to secondary malignancies and improve safety assessment.
CAR T-cell therapy, a promising treatment for blood cancers, has resulted in a few isolated cases of secondary malignancies suspected to be caused by the modified T cells. The analysis found that critical data for a robust causality assessment is often lacking, particularly regarding tumor samples for molecular analysis. Molecular tests, including the examination of gene shuttle, vector integration sites, and their oncogenic potential, play a crucial role in identifying the exact mechanism of these secondary cancers. The study calls for a standardized approach to causality assessment, considering the unique characteristics of gene therapy products, such as one-time treatments and permanent genetic modifications.
To address the challenges of assessing secondary T-cell malignancies as adverse reactions, the authors propose developing modified criteria for causality assessment. These new guidelines should incorporate molecular methods that detect vector integration and screen for oncogenic effects, enabling a deeper understanding of the risks associated with CAR T-cell therapy. Such improvements in the assessment process are vital for enhancing patient safety and ensuring that the benefits of CAR T-cell therapies are fully realized while minimizing the risks of long-term complications.
Link to the article: https://www.embopress.org/doi/full/10.1038/s44321-024-00183-2
References Berg, P., Ruppert-Seipp, G., Müller, S., Maurer, G. D., Hartmann, J., Holtick, U., Buchholz, C. J., & Funk, M. B. (2025). CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts. EMBO Molecular Medicine. https://doi.org/10.1038/s44321-024-00183-2
