Allogeneic dual-target CD19/BCMA CAR T-cell therapy (QT-019B) for refractory autoimmune hemolytic anemia Free

Background Refractory autoimmune hemolytic anemia (rAIHA) is characterized by severe, life-threatening hemolysis, and conventional therapies targeting B cells frequently fail to control the disease. Recent evidence suggests that autologous CD19-directed CAR-T cell therapy may offer a promising approach for rAIHA by inducing sustained, drug-free remission (Abstract 682, 2024 ASH). Nevertheless, the widespread application of autologous CAR-T therapies is constrained by their high cost and complex manufacturing requirements. To address these limitations, we have developed an allogeneic CAR-T cell product targeting both CD19 and BCMA, aiming to achieve an immune reset via comprehensive eradication of autoantibody-producing cells.

Methods In this investigator-initiated trial (NCT06733610), an accelerated titration design followed by a traditional 3+3 dose escalation methodology was implemented. Four patients diagnosed with rAIHA were administered QT-019B after standard lymphodepletion conditioning, consistingof fludarabine and cyclophosphamide.

Results As of July 31, 2025, four patients have completed the dose-limiting toxicity (DLT) observation, with dosing levels of 3×10⁵/kg (n=1), 1×10⁶/kg (n=2), and 3×10⁶/kg (n=1). Additionally, two more patients are pending enrollment at the 3×10⁶/kg dose level. The initial four patients who completed the DLT had follow-up durations of 7, 5, 4, and 2 months, respectively.

Patient 1 received a dose of 3×10⁵ cells/kg, which is a notably low dosage that may be insufficient to support the PK expansion of allogeneic CAR-T cells; however, no safety concerns were observed at this level. Consequently, a dose escalation to 1×10⁶ cells/kg was implemented.

Patient 2 reached a Cmax of 37,749 copies/µg DNA on Day 14 and fell below the lower limit of quantification (LLOQ; 100 copies/µg DNA) by Day 21. At baseline, his hemoglobin was 68 g/L, with elevated reticulocyte count, total bilirubin, indirect bilirubin, and lactate dehydrogenase (LDH) levels. The Coombs test was positive. Improvement of hemolysis was observed from Day 18, with all key markers returning to normal by Day 26, reached complete response (CR) and sustained through Day 150 without recurrence of hemolysis. Until 31st July, the patient reported no toxicities including fever (>38°C), CRS, ICANS, or infections. The planned Month 6 visit is planned in August 2025.

Patient 3, diagnosed with rAIHA, was treated at the escalated dose of 1×10⁶ cells/kg but unexpectedly did not exhibit robust in vivo PK expansion. A retrospective analysis identified several factors potentially contributing to this lack of response, including a medical history of recurrent systemic serious infections, an elevated baseline ferritin level approximately seven times the upper limit of normal (2130 ng/mL; ULN = 306 ng/mL), and high expression of HLA-C on peripheral blood mononuclear cells (PBMCs). These findings collectively suggest a state of immune overactivation in this patient.

Patient 4 attained a Cmax of 322,186 copies/µg DNA on Day 17, accompanied by a Grade 1 CRS. At baseline, the patient presented with a hemoglobin level of 66 g/L, alongside elevated reticulocyte count, total bilirubin, indirect bilirubin, and LDH levels. The Coombs test yielded a positive result. Indicators of hemolysis showed improvement from Day 14, as evidenced by normalization of bilirubin levels and a reduction in LDH. By the latest visit on Day 60, the patient's hemoglobin had increased to 110 g/L, with a marked amelioration of hemolytic activity.

At the ASH meeting, we will present aggregated data from all six patients, providing comprehensive evidence of immune reset. Additionally, we intend to discuss translational insights gained from patient 3, specifically regarding the effects of immune overactivation on allogeneic cell therapies and strategies to mitigate these impacts in protocol design.

Conclusions In summary, the allogeneic dual-target anti-CD19/BCMA CAR T-cell therapy (QT-019B) has shown promising clinical outcomes in the treatment of rAIHA. Moreover, the study provides important insights into the underlying causes of suboptimal in vivo PK expansion. These findings should be considered into the development of new protocols, as well as inform the advancement of other allogeneic CAR-T cell therapies.