Phase I Study of Allogeneic Anti-CD19 CAR-T Therapy for Patients with CD19+ Relapsed/Refractory Acute B-Lymphoblastic Leukemia

INTRODUCTION

Acute B-lymphoblastic leukemia (B-ALL) is a prevalent B-cell malignancy that often expresses the CD19 antigen, affecting all age groups. While CD19-targeted CAR-T cell therapy has shown remarkable clinical benefits, especially in relapsed/refractory B-ALL (R/R B-ALL), the widespread adoption of autologous CAR-T treatments is hindered by high costs and limited accessibility. To overcome these limitations, we have developed RD06-03, an allogeneic CAR-T product designed to enhance persistence and reduce the risk of host rejection. Engineered TCR/A knockout, protein Z overexpressing anti-CD19 CAR T cells (RD06-03) exhibited resistance to allogeneic rejection and enhanced anti-tumor effects without inducing graft-versus-host disease (GvHD). This innovative approach enables a CAR-T dosage that is a fraction of what is traditionally required for autologous treatments, potentially revolutionizing the cost-effectiveness of CAR-T cell therapy. Our phase 1 clinical trial (NCT06307600) aims to assess the safety and efficacy of RD06-03 in R/R B-ALL patients, offering a novel “off-the-shelf” solution to meet clinical need.

METHODS

Patients aged 3 to 70 years with CD19+ R/R B-ALL were eligible and sequentially enrolled in a “3+3” dose escalation study with three dosing groups (DL1: 1×10⁵ CAR⁺T cells/kg; DL2: 3×10⁵ CAR⁺T cells/kg; DL3: 5×10⁵ CAR⁺T cells/kg). All patients received a lymphodepletion regimen consisting of fludarabine (30mg/m²/day) and cyclophosphamide (500mg/m²/day) for three consecutive days (day -5 to day -3) before CAR-T infusion. Initial disease assessment was conducted on Day 28. Upon evaluating dose-limiting toxicity (DLT) across three dosing groups and establishing the maximum tolerated dose (MTD), the study will advance to case expansion with an appropriate dose level that balances safety and efficacy.

RESULTS

As of July 26, 2024, a total of 4 eligible patients with R/R B-ALL have been enrolled (1 in DL1 and 3 in DL2), with a median age of 48 years (range, 34 to 63). The median number of prior therapy lines was 3 (range, 2 to 8), and 1 patient had prior unrelated umbilical cord blood transplantation (UCBT) before enrollment. The median proportion of bone marrow blasts was 41.4% (range: 15% to 88.5%) among 4 patients. DLT, neurotoxicity and GvHD were not observed in the DL1 or DL2 dosing groups. Two patients at DL2 experienced cytokine release syndrome (CRS), which was mild and manageable (Grade 1, n=2). RD06-03 exhibited dose-dependent antileukemic activity with no response observed at DL1 by Day 28 post-infusion. Among evaluable patients at DL2, three achieved CR/CRi , resulting in an overall response rate (ORR) of 100% in this group. All these responders were negative for minimal residual disease (MRD), indicating a deep and complete response to the treatment. CAR-T expansion was not detected in the DL1 patient by qPCR, potentially due to the lower dosage, while all DL2 patients showed sustained expansion from Day 4, peaking between Day 7 and Day 10, with the longest persistence exceeding 6 weeks.

CONCLUSION

The allogeneic anti-CD19 CAR-T product RD06-03 exhibited a manageable safety profile and antileukemic effects in heavily pretreated R/R B-ALL patients. Further studies with an expanded population and extended follow-up periods are warranted to validate these preliminary findings.

No relevant conflicts of interest to declare.