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Assatova, Bimarzhan; Willim, Robert; Trevisani, Christopher; Haskett, Garrett; Kariya, Khyati Maulik; Chopra, Kusha; Park, Sung Rye; Tolstorukov, Michael Yevgeniy; McCabe, Sean M.; Duffy, Jessica; Louissaint, Abner; Huuhtanen, Jani; Bhattacharya, Dipabarna; Mustjoki, Satu; Koh, Min Jung; Powers, Foster; Morgan, Elizabeth A.; Yang, Lei; Pinckney, Brandy; Cotton, Matthew J.; Crabbe, Andrew; Ziemba, Jessica Beth; Brain, Ian; Heavican-Foral, Tayla B.; [...]

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes

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  • Medientyp: E-Artikel
  • Titel: KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes
  • Beteiligte: Assatova, Bimarzhan; Willim, Robert; Trevisani, Christopher; Haskett, Garrett; Kariya, Khyati Maulik; Chopra, Kusha; Park, Sung Rye; Tolstorukov, Michael Yevgeniy; McCabe, Sean M.; Duffy, Jessica; Louissaint, Abner; Huuhtanen, Jani; Bhattacharya, Dipabarna; Mustjoki, Satu; Koh, Min Jung; Powers, Foster; Morgan, Elizabeth A.; Yang, Lei; Pinckney, Brandy; Cotton, Matthew J.; Crabbe, Andrew; Ziemba, Jessica Beth; Brain, Ian; Heavican-Foral, Tayla B.; [...]
  • Erschienen: American Association for Cancer Research (AACR), 2024
  • Erschienen in: Clinical Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-23-3504
  • ISSN: 1078-0432; 1557-3265
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3−/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1− naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms.</jats:p> </jats:sec>