A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Overall response rate 20% (3/15 patients)

• Primary Outcome: Safety and tolerability of VCAR33

• Nnt Or Sensitivity: Number needed to treat: 5 patients for one response

• Confidence Interval: Not reported

Clinical Application

Limited to major transplant centres with CAR-T manufacturing capabilities and donor availability Would require TGA approval and PBS listing; limited to major transplant centres like Peter MacCallum, Royal Melbourne Hospital, Westmead. Currently no donor-derived CAR-T products approved in Australia Highly selected adults with relapsed/refractory CD33+ AML/MDS post-allogeneic transplant at specialised centres

Abstract

VCAR33, a donor-derived CD33-directed chimeric antigen receptor T-cell (CAR T) product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe preclinical characterization of the VCAR33 construct, which was optimized for long-term antitumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in arm A (bone marrow blasts ≥5%) at dose level 1 (DL1; 1 × 106 CAR+ Ts per kg) and 8 patients in arm B (bone marrow blasts <5%) at DL1 (n = 5) and DL2 (3 × 106 CAR+ Ts per kg; n = 3). The study ended for nonsafety reasons before escalation to DL3 (1 × 107 CAR+ Ts per kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all <grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 ≥grade 3) and 1 patient (6.7%) had grade 3 acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in arm A and 1 arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary antileukemic activity. This trial was registered at www.clinicaltrials.gov as #NCT05984199.

References

1. 1.Mushtaq, M. U., DiPersio, J. F., Azzi, J., Cooper, B. W., Koehne, G., Koura, D., Maakaron, J., Magenau, J., McClune, B., Rimando, J. C., Shah, N. N., Suh, H. C., Beuka, K., Sturrock, J., Nikam, M., Berglund, E., Hu, J., Keschner, Y., Etchin, J., Lydeard, J. R., Vasquez, M., O'Donnell, D., Mundelboim, G., Thosar, S., Canesin, G., Xavier-Ferrucio, J., Hyzy, S. L., Lloyd, D. M., Spink, K., Hummel, D., Lee-Sundlov, M. M., Scherer, J., Lin, M. I., Whangbo, J. S., & Muffly, L. S. (2026). A phase 1/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed/refractory AML after allogeneic HCT. Blood. https://doi.org/10.1182/blood.2025031053