CD19/22 CAR-T 细胞治疗儿童及年轻成人 B-ALL：1 期结果与新型双顺反子 CAR 的研发

Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19. 22. BB ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5. 4 to 34. 6 years, with B-ALL received CD19. 22. BB . The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71. 4% (10 of 14) in CAR-na ve patients.

Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80. 8% (95% confidence interval [CI]: 42. 4%-94. 9%) and 57. 7% (95% CI: 22. 1%-81. 9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19. 22. BB compared with EF1 -CD22. BB prompted laboratory investigations comparing EF1 vs MSCV promoters, which did not reveal major differences.

Limited CD22 targeting with CD19. 22. BB , as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19. 28 /CD22. BB construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19. 22. BB in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www. clinicaltrials. gov #NCT03448393).