CTA311, a universal anti-CD19 CAR t-cell therapy with improved persistence for patients with CD19+ relapsed/ refractory (R/R) b-cell acute lymphoblastic leukemia (B-ALL)

Abstract R/R B-ALL remains difficult to treat with a dismal prognosis, even in the era of autologous CAR-T and targeted therapies. Autologous CAR-T products have demonstrated significant remission rates but have been limited by several factors; manufacturing challenges and progressive disease while awaiting CAR-T products account for ~1-13%, and ~30% of failures to treat, respectively. For those that received therapy, response duration is limited with ~50% responders relapsing within 12 months; notably CAR-T in vivo persistence has been associated with response duration. These scenarios call for an “off-the-shelf” CAR-T product, which is safe and persistent for the treatment of leukemia. CTA311, is a CD-19 targeted “off-the-shelf” universal CAR-T product with T cell receptor and human leukocyte antigen class II knockout, as well as NK inhibitory molecule overexpression to prevent GvHD, and host immune rejection - leading to increased persistence. Patients (pts) diagnosed with R/R B-ALL were enrolled in a dose escalation study with dosing groups of 1×105 - 15×105 (CAR+ T cells/kg). All pts received a lymphodepletion regimen consisting of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/ m2/day) for 3 consecutive days (day -5 to -3) before CAR-T infusion (day 0). Disease was assessed on D28/month (M) 2/M3, and then every three months thereafter by bone marrow (BM) aspirate/biopsy. Complete remission (CR) is defined as BM blasts <5% with absolute neutrophil count ≥1,000/μL and platelet count ≥100,000/μL, CRi is CR with incomplete hematologic recovery. Duration of response (DOR), measured from initial response to relapse or death, was calculated using Kaplan-Meier statistics. Pharmacokinetics (PK) were measured using qPCR; minimal residual disease (MRD) was detected by flow cytometry (threshold >0.01%). As of July 10th, 2025, a total of 10 pts with R/R B-ALL have received CTA311 infusion in two sites in China; median age of 36 years (range, 18 - 63 years). The median prior therapy lines was 3 (range, 2 to 8), and 1 patient relapsed following umbilical cord blood transplantation. The median bone marrow blasts was 43% (range, 10% - 98.5%). CTA311 was well tolerated with no DLTs, neurotoxicity or GvHD observed. Seven (70%) pts experienced cytokine release syndrome (CRS), all of which were mild (Grade 1, n=7). CTA311 demonstrated encouraging antileukemic activity, with CR/CRi 75% (6/8 evaluable pts; 2 pts dropped out prior to disease assessment). MRD was undetectable in all responding pts at the time of assessment, indicating a deep response to the treatment. As of the cutoff date, median duration of DOR has not been reached, with the longest ongoing duration of 12.3M. Robust expansion and persistence were observed with median Cmax of 308332 copies/g DNA, median persistence of 24.5 days and longest persistence surpassing 3 months. These studies confirm the safety and preliminary antileukemic activity of CTA311 in pts with R/R B-ALL. Notably, CTA311's engineering enhances its safety, resistance to rejection and antileukemic activity without GvHD. CTA311 demonstrates robust persistence, achieving a 100% MRDneg CR/CRi, at doses lower than approved for autologous CAR-T, and mDOR not yet reached, while maintaining a manageable safety profile under standard lymphodepletion. Additional studies are planned to further confirm these initial findings.