IFNα Augments Clinical Efficacy of Regulatory T-cell Depletion with Denileukin Diftitox in Ovarian Cancer.

Autor:	Thibodeaux SR; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.; Department of Medicine, University of Texas Health San Antonio, Texas., Barnett BB; Tulane Medical School, Department of Medicine, New Orleans, Louisiana., Pandeswara S; Department of Medicine, University of Texas Health San Antonio, Texas., Wall SR; Department of Medicine, University of Texas Health San Antonio, Texas., Hurez V; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.; Department of Medicine, University of Texas Health San Antonio, Texas., Dao V; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas., Sun L; Department of Medicine, University of Texas Health San Antonio, Texas., Daniel BJ; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas.; Department of Medicine, University of Texas Health San Antonio, Texas., Brumlik MJ; Department of Medicine, University of Texas Health San Antonio, Texas., Drerup J; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas., Padrón Á; Department of Medicine, University of Texas Health San Antonio, Texas., Whiteside T; University of Pittsburgh and Hillman Comprehensive Cancer Center, Pittsburgh, Pennsylvania., Kryczek I; Tulane Medical School, Department of Medicine, New Orleans, Louisiana., Zou W; Tulane Medical School, Department of Medicine, New Orleans, Louisiana., Curiel TJ; The Graduate School of Biomedical Sciences, University of Texas Health San Antonio, Texas. curielt@uthscsa.edu.; Department of Medicine, University of Texas Health San Antonio, Texas.; Mays Cancer Center, University of Texas Health, San Antonio, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jul 01; Vol. 27 (13), pp. 3661-3673. Date of Electronic Publication: 2021 Mar 26.
DOI:	10.1158/1078-0432.CCR-20-4594
Abstrakt:	Purpose: Immunotherapy treats some cancers, but not ovarian cancer. Regulatory T cells (Tregs) impede anti-ovarian cancer immunity but effective human Treg-directed treatments are lacking. We tested Treg depletion with denileukin diftitox (DD) ± IFNα as ovarian cancer immunotherapy. Patients and Methods: Mice with syngeneic ID8 ovarian cancer challenge were treated with DD, IFNα, or both. The phase 0/I trial tested one dose-escalated DD infusion for functional Treg reduction, safety, and tolerability. The phase II trial added IFNα2a to DD if DD alone failed clinically. Results: DD depleted Tregs, and improved antitumor immunity and survival in mice. IFNα significantly improved antitumor immunity and survival with DD. IFNα did not alter Treg numbers or function but boosted tumor-specific immunity and reduced tumor Treg function with DD by inducing dendritic cell IL6. DD alone was well tolerated, depleted functional blood Tregs and improved immunity in patients with various malignancies in phase 0/I. A patient with ovarian cancer in phase 0/I experienced partial clinical response prompting a phase II ovarian cancer trial, but DD alone failed phase II. Another phase II trial added pegylated IFNα2a to failed DD, producing immunologic and clinical benefit in two of two patients before a DD shortage halt. DD alone was well tolerated. Adding IFNα increased toxicities but was tolerable, and reduced human Treg numbers in blood, and function through dendritic cell-induced IL6 in vitro . Conclusions: Treg depletion is clinically useful but unlikely alone to cure ovarian cancer. Rational treatment agent combinations can salvage clinical failure of Treg depletion alone, even when neither single agent provides meaningful clinical benefit. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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