First Human Trial of Novel Anti-CD19 CAR T-Cell Therapy Shows Promising Phase I Outcomes

Treatment with WZTL-002, a novel third-generation CD19-directed chimeric antigen receptor (CAR) T-cell agent for the treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma, did not induce severe cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity syndrome (ICANS) at all doses levels, as evaluated in a phase I dose-escalation trial.

The study’s authors, led by Robert Weinkove, PhD, of the Malaghan Institute of Medical Research in Wellington, New Zealand, stated their findings suggest “interposition of a TLR2 domain between CD28 and CD3ζ domains may reduce CAR T-cell–related ICANS risk while retaining efficacy.” The data were featured at the 65th ASH Annual Meeting and Exposition in San Diego, California.

This first in-human trial of WZTL-002 included 21 patients with lymphoma with a median age of 57 years (range, 23–70). The cohort predominantly had large cell histology (n=17) and had received a median of four prior lines of therapy, including autografts in 11 and allografts in one. At the data cutoff of June 14, 2023, all 21 patients had reached the primary analysis timepoint of three months after treatment.

Grade 3 or higher adverse events occurring in 10% or more of patients included neutropenia in 95%, lymphopenia in 57%, hypogammaglobulinemia in 57%, anemia in 43%, febrile neutropenia in 43%, thrombocytopenia in 24%, and tumor pain in 19%.

CRS of grade 1 or 2 was reported in 13 patients. Two grade 4 cytopenia dose-limiting toxicities occurred at day 21, both of which were reduced to grade 2 by day 90. The authors noted that a maximum tolerated dose was not reached, and a recommended phase 2 dose range of 0.5–1 × 10⁶/kg was established. Reportedly, WZTL-002 at the recommended phase 2 dose exhibited CAR T-cell expansion comparable to or greater than other CD19-directed agents.

Overall, Dr. Weinkove and colleagues said their data supported preclinical findings and noted that the dose-expansion cohort had been initiated to evaluate outpatient management and safety and efficacy of the CAR T-cell manufacturing process.

Reference

Weinkove R, George P, Fyfe R, et al. Phase 1 dose escalation trial of third-generation CD19-directed CAR T-cells incorporating CD28 and toll-like receptor 2 (TLR2) intracellular domains for relapsed or refractory B-cell non-Hodgkin lymphomas (ENABLE). Abstract #890. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12; San Diego, California.