Safety and Efficacy of CD 19 CAR T Cells (S1904) in Patients with RR B-ALL: A Pooled Analysis of Two Early-Phase Trials
Authors: Huang Xiao Jun , Lv Meng , Lu Peihua , Luo Jianmin , Kuang Na 
Published: December 2024

S1904 is a chimeric antigen receptor (CAR)-modified T-cell therapy designed to specifically target CD19 in relapsed or refractory B-cell acute lymphoblastic leukemia (RR B-ALL). By employing the MND promoter upstream, the S1904 CAR gene demonstrates lower surface CAR molecule density but achieves better transduction rates and superior antitumor effects in both in vitro and in vivo studies compared to the EF1α promoter. With the same target-to-effector ratio, these cells secrete fewer cytokines. Consequently, S1904 maintains a more durable antitumor effect in vivo while reducing the risk of cytokine release syndrome. Additionally, using Senlang's proprietary production platform, the production cost of S1904 has been significantly reduced-by up to 90% compared to existing CAR T products-and has achieved a 100% success rate in manufacturing. This report presents a pooled analysis of results from two early-phase clinical trials evaluating the efficacy of S1904 in patients with RR B-ALL.

Patients and Methods

These two open-label phase I trials (CTR20221359，NCT04626726) have a similar target population and evaluation schedules. The primary objective was to assess the safety and tolerability of S1904, while secondary objectives included efficacy, pharmacokinetics and immunogenicity. Key enrolment criteria included CD 19+ RR B-ALL patients (aged 3 years and above) who had failed multiple therapy lines and had adequate organ functions.

Upon enrollment, patients received lymphodepleting chemotherapy with fludarabine (25mg/m2 daily for 3 days) and cyclophosphamide (500mg/m2 daily for 2 days), followed by a single infusion of S1904. The dose cohorts were 0.3×106/kg, 0.5×106/kg and 1×106/kg CAR+ T cells.

Results

The combined cohort comprised 32 RR B-ALL patients with median age of 19 years (range: 3-66), including 20 males (62.5%) and 12 females (37.5%). The median number of prior therapy lines was 2 (range:1 to 5), with 13 patients (40.7%) having three or more lines of therapy.

The most common treatment-emergent adverse events of grade 3 or higher were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) was reported in 28 patients (87.5%) with the majority (83.3%) being grade 1 or 2, and only two patents (6.3%) experienced grade 3 CRS. All CRS cases were rapidly resolved with conventional interventions, including tocilizumab and steroids. The median time to CRS onset was 8 days (range 1-11) with a median duration of 4 days (range 1-24). Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in two patients, both of whom recovered quickly with symptomatic treatments. Head CT scans for these patients were negative from hemorrhagic focus.

The overall response rate (CR and CRi) was 96.9%. The median duration of response was 11.73 months (95% CI, 3.75 to not reached), and the median progression-free survival (PFS) was 5.95 months (95% CI, 2.96 to not reached). Median overall survival (OS) has not yet been reached.

Following CAR-T infusion, 15 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), while 17 patients did not. The median PFS was longer in patients who received allo-HSCT compared to those who did not (not reached vs. 5.95 months, P=0.0154). However, median OS did not show statistical significance.

Conclusion

In RR B-ALL patients who had progressed after multiple previous lines of therapy, S1904 demonstrated a tolerable safety profile and promising anticancer efficacy. With Senlang's cost-effective manufacturing process, making cell therapy accessible to most patients is not an unattainable goal. Additionally, the observed benefits of combining CD19 CAR-T therapy with bridging allo-HSCT warrant further confirmation in future studies.