Michaela Su-Fern Seng, Zexi Guo, Kai Soon Ng, Shui Yen Soh, Francesca Wei Inng Lim, Liang Piu Koh, William Yk Hwang, Aloysius Yl Ho, Yeh Ching Linn, Esther Hian Li Chan, Michelle L M Poon, Lip Kun Tan, Mickey Bc Koh, Tun Kiat Ko, Jia Yu, King Pan Ng, Teck Guan Soh, Jason Yongsheng Chan, Joe Poh Sheng Yeong, Rimas J Orentas, Wing Leung
Durable remissions after anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory B-lineage acute lymphoblastic leukaemia are limited by antigen escape and T-cell dysfunction. The tandem CAR22-19/LTG2737 construct links human-derived anti-CD22 and anti-CD19 scFvs to CD8 hinge/transmembrane, 4-1BB, and CD3ζ domains. In a multicentre phase I/II trial, all patients (n=11; 7 children, 4 adults) achieved complete remission by Day 28 (91% minimal residual disease-negative). At a 34-month median follow-up, median overall survival (OS) and leukaemia-free survival (LFS) were not reached. The 12-month OS was 82% (95%CI: 45%-95%) and LFS was 64% (95%CI: 30%-85%) without consolidative transplantation. Immune-effector cell-associated toxicities included cytokine release syndrome, haematotoxicity, and haemophagocytic lymphohistiocytosis-like syndrome. De novo CD19 escape caused one relapse. Exploratory multi-omic profiling linked durable response to higher CD22 antigen density on blasts; pre-infusion CD4 CAR-T cells expressing IL7Rα, LEF1, BACH2, and TCF7 but lower FOXP3; post-infusion NK-like effector CAR-T expansion; and central-memory CAR-T pool maintenance.