A first-in-human study of CT0596, an allogeneic CAR T-cell therapy targeting BCMA, in patients with relapsed/refractory multiple myeloma Free

Introduction Universal CAR T-cell therapy addresses key challenges of autologous CAR T, including high cost, time-consuming, personalized manufacturing and manufacturing failure risks. CT0596 is an allogeneic BCMA-targeting CAR T-cell therapy developed on the THANK-u Plus^TM platform. It incorporates the knockout of NKG2A, TRAC and B2M genes to mitigate T/NK cell-mediated graft-versus-host disease and host immune rejection, with additional gene editing to further hinder NK cell-mediated rejection from host.

Methods This is a first-in-human, open-label, Phase I, exploratory study (NCT06718270) to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CT0596 in relapsed/refractory multiple myeloma (RR MM) and plasma cell leukemia (PCL) patients. RR MM (≥3 prior lines of therapy including at least one proteasome inhibitor and one immunomodulatory) or PCL patients (≥1 prior lines) were eligible. Following lymphodepletion regimen consisting of fludarabine (30 mg/m²) and cyclophosphamide (500 mg/m²) for 3 consecutive days, CT0596 was administered at escalating doses of 1.5×10⁸, 3.0×10⁸ or 4.5×10⁸ CAR-positive T cells using i3+3 dose-escalation design.

Results As of 24 June 2025, 8 R/R MM patients were infused, with a median age of 63.5 years (range 49-70) and median prior lines of therapy of 4.5 (range 3-9). Five patients were triple-class exposed (PI, IMiD and anti-CD38) and 5 had prior autologous stem cell transplantation history. Disease subtypes included IgA (n=4), IgG (n=2), and kappa light chain (n=2). Most patients had advanced disease (ISS Stage III: n=5; R-ISS Stage III: n=3), and 1 had extramedullary soft disease. Of 4 patients undergoing cytogenetics examination, 1 had high-risk cytogenetic.

Six patients received full dose of lymphodepletion, and 2 reduced lymphodepletion dose by 30% of cyclophosphamide and 25% of fludarabine and cyclophosphamide, respectively, due to severe hematological toxicity and decreased creatinine clearance. One patient was infused with 1.5 × 10⁸ cells, 5 with 3.0× 10⁸ cells, and 2 with 4.5 × 10⁸ cells.

No dose-limiting toxicities, treatment discontinuations or deaths were observed. Four patients experienced grade 1 cytokine release syndrome, and all recovered within 2-10 days. Grade≥3 treatment-related adverse events included: leukopenia (n=8), neutropenia (n=7), lymphopenia (n=8), thrombocytopenia (n=3), and anemia (n=2). All Grade≥3 adverse events were hematology toxicity, and the majority recovered within 30 days.

Eight infused patients were all evaluable for efficacy, the median follow-up time was 2.56 months (range 0.9, 5.9). Five patients achieved PR or above: 3 CR/sCR (all 3 received full lymphodepletion dose), 1 PR and 1 VGPR. Six patients achieved MRD negativity at Week 4. No patients got progression disease, and Pat 01 has ongoing sCR and MRD negative for nearly 6 months. CAR T cell expansion was observed in all 8 patients.

Conclusion These initial results from this study of CT0596 support the feasibility and safety of allogeneic CAR T-cell therapy for RR MM, thereby warranting further exploration in larger-scale trials.