具有延长持续时间与多基因逻辑功能的自扩增 RNA CAR-T 细胞疗法

Chimeric antigen receptor T (CAR-T) cell therapy is transforming the treatment landscape of hematological malignancies.

However, manufacturing with integrating viral vectors is costly, slow, and carries risks including insertional mutagenesis, prolonged B cell aplasia, and other long-term toxicities. Expression of CAR with mRNA can reduce cost, manufacturing timelines, and improve safety.

However, the short-lived expression necessitates frequent repeat dosing.

Here, we describe a modified self-amplifying RNA (saRNA) platform for engineering CAR T cells with prolonged CAR expression and enhanced durability of tumor control relative to mRNA CAR T cells. In an acute lymphoblastic leukemia (ALL) xenograft model, saRNA CAR T cells achieve superior tumor suppression and prolong survival.

Further, a single-strand modified saRNA supports the co-expression of multiple proteins, enabling the construction of advanced CAR systems, such as OR- and AND-gated logic CAR T cells.

Together, these results highlight saRNA as a powerful and versatile platform for CAR T cell engineering with favorable safety, efficacy, and accessibility.