KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes.
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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, Iqbal Javeed, Nemec Ronald, Rider Anna Baird, Ford Josie Germain, Koh Min Ji, Scanlan Nora, Feith David J, Loughran Thomas P, Kim Won Seog, Choi Jaehyuk, Roels Juliette, Boehme Lena, Putteman Tom, Taghon Tom, Barnes Jeffrey A, Johnson P Connor, Jacobsen Eric D, Greenberg Steven A, Weinstock David M, Jain Salvia
Аннотация
EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.
RESULTS: 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.
CONCLUSIONS: 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. See related commentary by Varma and Diefenbach, p. 2300.