Mana Alshehri, Senior Chief Scientific Expert at the Saudi Food and Drug Authority (SFDA), shared on LinkedIn:
“Can inherited genetics influence the efficacy and safety of CAR-T therapy?
A new study published in Science Immunology provides compelling evidence that germline genetic variants may help explain why CAR-T cells expand effectively in some patients but cause severe toxicity in others.
Researchers analyzed whole-genome sequencing data from more than 200 patients with aggressive lymphoma treated with axicabtagene ciloleucel in the ZUMA-1 and ZUMA-7 trials.
Key findings included:
- PTPN22 variants were strongly associated with greater CAR-T cell expansion – an important correlate of clinical activity.
- ADAMTSL3 variants were associated with protection from treatment-related toxicity across both trials.
- Potentially damaging STXBP2 variants were linked to hyperinflammatory toxicity in ZUMA-1, although this association was not reproduced in ZUMA-7, highlighting the need for further validation.
In summary: the study showed that patient’s inherited genome may influence the biological characteristics of the final CAR-T product.
These findings could eventually support improved patient risk stratification, toxicity monitoring, CAR-T engineering and clinical-trial design.
A significant step toward integrating genomics, precision medicine and engineered immune-cell therapy.”
Title: Genomic correlates of clinical CAR T cell activity
Authors: Mark B. Leick, Baihe Sun, Filippo Birocchi, Kathleen M. E. Gallagher, Alexandra Bratt, Seunghun Han, Grace Martin, Harrison J. Silva, Rebecca C. Larson, Tyler M. Chinsky, Hoyin Chu, Christopher R. Reilly, Michael C. Kann, Bryan D. Choi, Sabrina Camp, Riaz Gillani, Merle Phillips, Tamina Kienka, Stefanie R. Bailey, Charlotte E. Graham, Max Jan, Nicholas S. Moore, Nora Horick, Justin Budka, Simone Filosto, Chad M. Williams, Ali Hosseini Rad, Rhine R. Shen, Eliezer Van Allen, Saud Aldubayan, and Marcela V. Maus
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