MANY MINDEDGenetic markers hint at who will react badly to CAR-T therapy
Researchers analyzing patients from clinical trials of Kite Pharma's CAR-T therapy Yescarta have identified genetic signatures linked to toxicity risk. The study, published in Science Immunology, drew on data from the Zuma-1 and Zuma-7 trials of axicabtagene ciloleucel in pretreated lymphoma patients. It was led by Mark Leick of Massachusetts General Hospital, who began the project in 2018 in Marcela Maus's lab. Kite is owned by Gilead Sciences.
The team found that all six Zuma-1 patients with function-knocking-out mutations in the STXBP2 gene experienced toxicity, though no such relationship appeared in Zuma-7. A genome-wide scan turned up protective variants of ADAMTSL3 associated with lower toxicity, and variants of PTPN22, a T-cell activity regulator, were linked to how much CAR-T cells proliferated after infusion, a finding confirmed across both trials.
CAR-T therapies can be powerful but carry serious, sometimes dangerous side effects that limit who can safely receive them. Being able to flag high-risk patients from their genetics, and potentially engineer cells to reduce toxicity, would make these treatments safer and deployable to more people. Carl June, a CAR-T pioneer not involved in the work, noted that germline genetics strongly shape expansion and toxicity.
The key limit: the study covered only patients of European descent, since they made up the vast majority of trial enrollment, and researchers said they lacked the numbers to analyze non-European patients. The proposed use of PTPN22 knockouts in manufacturing is a possibility, not a demonstrated protocol.
Source: Fierce Biotech