WZTL-002 CAR T Cells Show Potential in Treatment of Relapsed or Refractory B-Cell NHL

A third-generation, CD19-directed chimeric antigen receptor (CAR) T-cell therapy demonstrated low rates of common CAR-T–related toxicities and elicited complete responses (CRs) comparable to commercially available second-generation CAR T-cell agents in patients with relapsed or refractory B-cell non-Hodgkin lymphomas (NHL).

Thirty patients with B-cell NHL treated with the novel agent WZTL-002 in the phase 1 ENABLE-1 study (NCT04049513) are the source of these findings, which were presented in a poster by Robert Weinkove, MBBS, PhD, and colleagues at the 66^th American Society of Hematology Annual Meeting & Exposition. The common CAR T-cell–related toxicities seen at low rates in ENABLE-1 were immune effector cell–associated neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), and immune effector cell–associated hematotoxicity (ICAHT).

WZTL-002 was administered to study patients at 5 × 104 to 1×10⁶ viable CAR⁺ cells/kg recipient weight in the 3+3 dosing cohort (n=21). In an outpatient setting, WZTL-002 at 0.5 to 1×10⁶ CAR⁺ cells/kg, the recommended phase 2 dose, was administered (n=9). During the period between leukapheresis and lymphodepletion, some patients underwent bridging therapy consisting of fludarabine 30 mg/m² per day and cyclophosphamide 500 mg/m² per day for three days. CAR T cells were administered to patients two days after bridging therapy.

The study population had a median age of 58.5 years (range, 22–72) and was largely female (33%). Patients came from Europe (73%), Polynesia (23%), and Asia (3%). The patients had received a median of three prior lines of therapy.

WZTL-002 yielded a CR rate of 52% in the 21-patient dose escalation cohort and 56% in the 6-patient dose expansion cohort. Of those treated at the recommended phase 2 dose, the WZTL-002 had a geometric mean mean CAR T-cell level of 29,515 transgenes/μg genomic DNA, and CARs remained detectable at day 90 in 14 patients (88%).

The adverse events  of grade 3 or higher that occurred in 10% of recipients or more included lymphopenia (100%), neutropenia (97%), hypogammaglobulinemia (53%), febrile neutropenia (50%), thrombocytopenia (40%), anemia (30%), and tumor pain (20%).

Only one patient (3%) developed ICANS, which was resolved spontaneously according Weinkove et al. Regarding CRS, grade 1/2 events occurred in 17 patients (57%), and no events of grade 3 or higher were observed. Of the patients who had CRS, nine (30%) received tocilizumab and three (10%) received dexamethasone as treatment. No patients in the study needed intensive care within 28 days of receiving WZTL-002.

Cases of grade 1/2 ICAHT were observed in six patients (20%), and four patients (13%) experienced grade 3/4 ICAHT.

The data indicate that outpatient CAR T-cell treatment of B-cell NHL is possible and may decrease treatment costs and improve the patient experience of CAR T-cell therapy, Weinkove et al noted in conclusion.

WZTL-002 is also undergoing clinical investigation for the treatment of relapsed or refractory large B-cell lymphoma in the phase 2 ENABLE-2 study (NCT06486051).

REFERENCE

Weinlove R, George P, Fyfe R, et al. A phase 1 dose escalation and expansion trial of third-generation CD19-directed CAR T-cells incorporating CD28 and toll-like receptor 2 (TLR2) co-stimulation for relapsed or refractory B-cell non-Hodgkin lymphomas (ENABLE-1). Abstract #2067. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.