A systematic review and meta-analysis of shRNA-IL-6-engineered CAR-T cells for B-cell Acute Lymphoblastic Leukemia: a stepping stone towards risk-free immunotherapy

Clinical application of chimeric antigen receptor (CAR)-T cells, especially those targeting CD19, stands as a breakthrough in treating relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Yet, preventing immune-related adverse events (IrAEs), like severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANs), remains a significant concern. This meta-analysis looked at the efficacy and safety of IL-6 knockdown CAR-T therapy. The study's primary outcomes included the incidence of CRS, ICANS, and patient number achieving an early complete response (CR) and overall response rate (ORR) at one-month post-infusion of anti-CD19 shRNA-engineered CAR-T cells. Random-effects model was used to estimate summary effects. Certainty of evidence was assessed using GRADE. Out of 275 studies screened, 7 studies were eligible (n=178 patients). The pooled ORR and CR rates were 88% (95% CI,81-92) and 84% (95% CI,78-89), respectively, with no heterogeneity detected. Among 147 patients, 116 (78%, 95% CI,68-85) developed CRS, whereas 46 (28%, CI,21-35%) out of 178 were affected by severe grades (≥3). While ICANS were detected in 13 out of 159 patients (13%, 95% CI,2-51%, I2=69.5%), three studies confirmed the absence of severe grade ICANs. According to GRADE assessment, current analysis presents low certainty of evidence supporting investigated outcomes, except for ICANS (any grade) that was deemed very low. More importantly, as all included studies were conducted in China, the findings may not be readily generalizable to other healthcare systems and ethnically diverse populations. Therefore, our confidence in the effect estimates is limited and it may vary from true estimates.