The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas.

Autor:	Rosario M; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Department of Pathology/Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri., Liu B; Altor BioScience Corporation, Miramar, Florida., Kong L; Altor BioScience Corporation, Miramar, Florida., Collins LI; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri., Schneider SE; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Chen X; Altor BioScience Corporation, Miramar, Florida., Han K; Altor BioScience Corporation, Miramar, Florida., Jeng EK; Altor BioScience Corporation, Miramar, Florida., Rhode PR; Altor BioScience Corporation, Miramar, Florida., Leong JW; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Schappe T; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Jewell BA; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Keppel CR; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Shah K; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Hess B; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Romee R; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Piwnica-Worms DR; Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri. Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas., Cashen AF; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Bartlett NL; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri., Wong HC; Altor BioScience Corporation, Miramar, Florida., Fehniger TA; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. tfehnige@wustl.edu.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Feb 01; Vol. 22 (3), pp. 596-608. Date of Electronic Publication: 2015 Sep 30.
DOI:	10.1158/1078-0432.CCR-15-1419
Abstrakt:	Purpose: Anti-CD20 monoclonal antibodies (mAb) are an important immunotherapy for B-cell lymphoma, and provide evidence that the immune system may be harnessed as an effective lymphoma treatment approach. ALT-803 is a superagonist IL-15 mutant and IL-15Rα-Fc fusion complex that activates the IL-15 receptor constitutively expressed on natural killer (NK) cells. We hypothesized that ALT-803 would enhance anti-CD20 mAb-directed NK-cell responses and antibody-dependent cellular cytotoxicity (ADCC). Experimental Design: We tested this hypothesis by adding ALT-803 immunostimulation to anti-CD20 mAb triggering of NK cells in vitro and in vivo. Cell lines and primary human lymphoma cells were utilized as targets for primary human NK cells. Two complementary in vivo mouse models were used, which included human NK-cell xenografts in NOD/SCID-γc (-/-) mice. Results: We demonstrate that short-term ALT-803 stimulation significantly increased degranulation, IFNγ production, and ADCC by human NK cells against B-cell lymphoma cell lines or primary follicular lymphoma cells. ALT-803 augmented cytotoxicity and the expression of granzyme B and perforin, providing one potential mechanism for this enhanced functionality. Moreover, in two distinct in vivo B-cell lymphoma models, the addition of ALT-803 to anti-CD20 mAb therapy resulted in significantly reduced tumor cell burden and increased survival. Long-term ALT-803 stimulation of human NK cells induced proliferation and NK-cell subset changes with preserved ADCC. Conclusions: ALT-803 represents a novel immunostimulatory drug that enhances NK-cell antilymphoma responses in vitro and in vivo, thereby supporting the clinical investigation of ALT-803 plus anti-CD20 mAbs in patients with indolent B-cell lymphoma. (©2015 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu