Denileukin Diftitox Shows Promise Before CAR-T Therapy in High-Risk DLBCL
A phase 1 trial shows denileukin diftitox administered before CAR-T therapy has a favorable safety profile and encouraging efficacy in high-risk DLBCL patients, with an 86% overall response rate and 77% one-year progression-free survival. The treatment demonstrated consistent regulatory T-cell depletion, supporting its immunomodulatory mechanism. Larger controlled studies are needed to confirm these preliminary findings.
Administration of denileukin diftitox-cxdl prior to CD19-directed CAR-T therapy demonstrated a favorable safety profile and encouraging early efficacy signals in high-risk relapsed or refractory diffuse large B-cell lymphoma (DLBCL), although conclusions regarding comparative effectiveness remain limited by the small, phase 1 design. Investigators reported high response rates alongside consistent pharmacodynamic evidence of regulatory T-cell (Treg) depletion, supporting further evaluation of this immunomodulatory strategy.
In the open-label, dose-escalation phase 1 trial (NCT04855253), 14 patients with adverse prognostic features, including double or triple hit genetics, primary refractory disease, and extranodal involvement, received a single dose of denileukin diftitox-cxdl at 5, 7, or 9 µg/kg prior to low-dose chemotherapy and subsequent infusion of commercially available CD19-directed CAR-T products. All enrolled participants completed treatment and proceeded to CAR-T infusion.
At 1 month, the overall response rate was 86%, comprising 57% complete responses and 29% partial responses. One-year progression-free survival was 77% (95% CI, 43-92%), and overall survival was 84% (95% CI, 49-96%). While these findings suggest a potential augmentation of CAR-T activity, the study was not powered for efficacy, and no formal statistical comparisons were performed.
Pharmacodynamic analyses demonstrated depletion of circulating Tregs in all but 1 patient, with a median reduction of 24 cells/µL (range, 8-65). The nadir occurred approximately 24 hours following administration, consistent with the proposed mechanism of enhancing CAR-T efficacy through modulation of the immunosuppressive tumor microenvironment.
Treatment was well tolerated, with no dose-limiting toxicities observed up to 9 µg/kg and no grade 3 or higher drug-related immune adverse events or infusion reactions. Reported toxicities included grade 1 to 2 capillary leak syndrome, fever, and transient transaminase elevations. Grade 3 cytopenias were consistent with expected lymphodepletion. CAR-T-associated cytokine release syndrome occurred in 43% of patients (all grade 1-2), and immune effector cell-associated neurotoxicity syndrome was reported in 21%, predominantly low grade.
DLBCL remains the most common subtype of non-Hodgkin lymphoma, accounting for approximately 30% to 40% of cases in the United States, with up to 40% of patients experiencing relapsed or refractory disease after frontline therapy. Outcomes are particularly poor in high-risk populations, underscoring the need for strategies that enhance CAR-T efficacy. Denileukin diftitox-cxdl, an IL-2 receptor-targeted fusion toxin approved for cutaneous T-cell lymphoma, represents a biologically plausible approach through selective Treg depletion.
These preliminary data indicate that integrating denileukin diftitox-cxdl into pre-CAR-T lymphodepletion is feasible and biologically active. Larger, controlled studies are warranted to determine whether this approach improves durable responses and long-term survival outcomes.