Engineering Non-Activated CAR T Cells for Improved Functional Persistence
Durgin JS, Seo SH, Kazmi S, et al. Single-Day Nonactivated IL-18-Armed CAR T Cells Establish a Durable, Stemlike State With Enhanced Persistence. Blood. 2026; (doi: 10.1182/blood.2026033460).
In vitro and in vivo profiling, along with transcriptomic and metabolomic analyses, showcase the potential of non-activated chimeric antigen receptor (CAR) T-cells as an alternative for tumors that do not respond to conventional CAR T. Manufactured in a single day, the absence of T-cell receptor activation keeps the cells in a naive-like, stem-like, and durable state. The non-activated cells also are reinforced with interleukin-18 — a pro-inflammatory cytokine that, when released by the cells, improves T-cell function through greater persistence, metabolic fitness, and resistance to exhaustion. Researchers validated the CART-IL18 T cells in xenograft models of lymphoma, leukemia, and pancreatic cancer, all of which signaled robust anti-tumor efficacy.