Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma.

Autor:	Hamlin PA; Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, New York., Musteata V; Institute of Oncology, ARENSIA EM, Chisinau, Republic of Moldova., Park SI; Levine Cancer Institute, Charlotte, North Carolina., Burnett C; Molecular Templates, Inc., Jersey City, New Jersey., Dabovic K; Molecular Templates, Inc., Jersey City, New Jersey., Strack T; Molecular Templates, Inc., Jersey City, New Jersey., Williams ET; Molecular Templates, Austin, Texas., Anand BS; Molecular Templates, Austin, Texas., Higgins JP; Molecular Templates, Austin, Texas., Persky DO; University of Arizona Cancer Center, Tucson, Arizona.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2022 May 05; Vol. 2 (5), pp. 307-315. Date of Electronic Publication: 2022 May 05 (Print Publication: 2022).
DOI:	10.1158/2767-9764.CRC-22-0056
Abstrakt:	MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL ( n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events. Significance: This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising. Competing Interests: P.A. Hamlin reports personal fees from Calithera, Karyopharm, Sandoz, and personal fees from Juno Therapeutics outside the submitted work. V. Musteata reports other from ARENSIA EM during the conduct of the study. S.I. Park reports grants and personal fees from BMS and Seattle Genetics; non-financial support from Rafael Pharma; personal fees from G1 Therapeutics, Teva, Gilead, Morphosys, and personal fees from Epizyme outside the submitted work; grants from Takeda. C. Burnett was a paid employee of Molecular Templates at the time the work was performed. K. Dabovic reports employment with the sponsor, Molecular Templates. T. Strack reports personal fees from Molecular Templates during the conduct of the study and personal fees from Molecular Templates outside the submitted work. E.T. Williams was employed by Molecular Templates for these efforts. J.P. Higgins reports grants from Cancer Prevention & Research Institute of Texas during the conduct of the study; personal fees from Molecular Templates outside the submitted work. D. Persky reports personal fees from Morphosys, Debiopharm, Karyopharm, Cellectar, Epizyme, ADC Therapeutics, Genentech, Beigene, Eli Lilly, Abbvie, and personal fees from TG Therapeutics outside the submitted work. No other disclosures were reported. (© 2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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