Phase I study of NPB5005-V283 in patients with relapsed/refractory multiple myeloma Free

Background: Chimeric antigen receptor (CAR)-T cell therapies have produced durable antitumor response for the treatment of relapsed and refractory hematological malignancies. The remarkable efficacy is achieved through redirecting T cell activation and cytolytic activity to tumor associated antigens. However, due to large-scale and non-physiological T cell activation, CAR-T cells treatment can cause high incidence of potentially life-threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), requiring frequent therapeutic intervention. While toxicity prevention and mitigation strategies have enhanced CAR-T therapy safety to make it more feasible and accessible to broader patients, development of novel CAR formats with favorable cellular and toxicity profiles remains the desired goal.

NPB5005-V283 is a novel autologous BCMA targeting CAR-T. The CAR is made of an extracellular nanobody, a CD8 transmembrane domain, a truncated 3^rd generation costimulatory domain (3.5 gen) composed of ICOS in tandem with N terminal-deleted 4-1BB signaling domains (ICOS-BBt, delivering more potent costimulatory signal than either 2^nd or wild-type 3^rd generation constructs), and a truncated CD3Zt containing one of three ITAM motifs to attenuate CAR-T cell overactivation, cytokine production, and exhaustion while maintaining active in vitro and in vivo antitumor activities. The novel combination of a 3.5-gen more potent costimulatory domain with a significantly truncated CD3Zt lays the foundation for the next generation of highly effective CAR Ts with controlled output of CRS and ICANS.

Methods: Study NPB5005-V283 is an investigator-initiated, first-in-human, single center, single-arm, open-label, 3+3 dose-escalation clinical trial approved by Ruijin Hospital Ethics Committee of Shanghai Jiaotong University School of Medicine (2023, IRB Approval No. 446). The clinical study is to evaluate the safety, tolerability, and efficacy of NPB5005-V283 cell injection in the treatment of relapsed/refractory multiple myeloma patients. The patients have received at least 3 prior lines of therapy. The NPB5005-V283 CAR was introduced into autologous T cells through lentiviral transduction and cells were expanded ex-vivo to the intended dose. Patients are administered infusion of NPB5005-V283 following lymphodepletion by fludarabine 30 mg/m² and cyclophosphamide 300 mg/m² daily for 3 days. Three dose levels at 1.5, 3.0, and 6.0 x 10⁶ CAR-Ts/kg are to be evaluated in 15 to 27 RRMM patients. The first patient in each dose group receives a split dose of 20%, 30%, and 50% on days 0, 2, and 6, respectively, while the rest receive a single dose. The primary endpoints assess the dose-limiting toxicities of CRS and ICANS using ASTCT consensus grading. The secondary endpoints include measurements of minimal residual disease (MRD), depth and duration of clinical response according to the IMWG Uniform Response Criteria, progression-free survival (PFS), and overall survival (OS).

Results: As of July 31, 2025, 4 patients of Han ethnicity were enrolled. 2 male sex (50%), median age was 62 years (range 50–73), median time from MM diagnosis was 4.2 years (range 3.5-5), received median 4.5 prior lines of treatment (range 3-6), 2 (50%) patients had high-risk cytogenetics, 1(25%) had extramedullary disease, 1(25%) had high tumor burden of 81% BMPCs,

Products had been successfully manufactured for all patients. Patients received bridging therapy between apheresis and infusion. Average time to infusion was 54 days (range 33-107). 3 patients received the dose of 1.5 x 10⁶ CAR-T cells/kg per protocol. Patient 4 was the first to be enrolled in the escalating dose of 3.0 x 10⁶ CAR-T cells/kg. The patient received first infusion of 20% dose after lymphodepletion per protocol. Next day, the patient had shown flu infection in the test, so the planned second infusion was postponed. The patient subsequently went through treatment of flu infection and emerging fever. 10 days after the first infusion, the patient received a non-conforming second infusion of 30% dose. In total, patient 4 ended up receiving a sum of half of the intended dose 3.0 x 10⁶ CAR-T cells/kg.

Median follow-up after NPB5005-V283 infusion was 3 months (range, 1-6 months). Enrollment and follow-up are ongoing and updated data will be presented.