Safe and potent anti‐CD19 CAR T‐cells with shRNA‐IL‐6 gene silencing element in patients with refractory or relapsed B‐cell acute lymphoblastic leukemia

Abstract 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.