含 shRNA-IL-6 基因沉默元件的安全强效抗 CD19 CAR-T 细胞在复发/难治性 B 细胞急性淋巴细胞白血病患者中的应用

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy.

We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade 3 CRS occurred in 14. 89% (7/47) of the ssCART-19 group versus 37. 5% (15/40) in the cCART-19 group ( p = 0. 036). ICANS occurred in 4. 26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group.

Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91. 49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 ( p = 0. 999). With a median follow-up of 21. 9 months, cumulative nonrelapse mortality was 10. 4% for ssCART-19 and 13.

6% for cCART-19 ( p = 0. 33). Median overall survival was 37. 17 months for ssCART-19 and 32. 93 months for cCART-19 ( p = 0. 40). Median progression-free survival was 24. 17 months for ssCART-19 and 9. 33 months for cCART-19 ( p = 0. 23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.