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ccr-23-0916_supplementary_figure_s3_suppfs3.pdf (416.42 kB)

Supplementary Figure S3 from Axicabtagene Ciloleucel in Combination with the 4–1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11

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posted on 2023-10-13, 07:42 authored by Michael D. Jain, David B. Miklos, Caron A. Jacobson, John M. Timmerman, Jennifer Sun, Jenny Nater, Xiang Fang, Ankit Patel, Madison Davis, Darren Heeke, Tan Trinh, Mike Mattie, Frank Neumann, Jenny J. Kim, Christina To, Simone Filosto, Ran Reshef

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ARTICLE ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4–1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy. In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose, 2 × 106 cells/kg) plus utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics. No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10. Utomilumab-mediated 4–1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4–1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

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