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

Clin Cancer Res. 2024 Jun 3;30(11):2514-2530. doi: 10.1158/1078-0432.CCR-23-3504.

Abstract

Purpose: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.

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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use
  • Cell Line, Tumor
  • Humans
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lectins, C-Type* / antagonists & inhibitors
  • Lectins, C-Type* / immunology
  • Lectins, C-Type* / metabolism
  • Lymphoma, T-Cell / drug therapy
  • Lymphoma, T-Cell / immunology
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell / therapy
  • Mice
  • Receptors, Immunologic* / antagonists & inhibitors
  • Receptors, Immunologic* / immunology
  • Receptors, Immunologic* / metabolism
  • Xenograft Model Antitumor Assays*

Substances

  • KLRG1 protein, human
  • Receptors, Immunologic
  • Lectins, C-Type
  • Antibodies, Monoclonal