KIR3DL2 IS EXPRESSED IN PERIPHERAL T‐CELL LYMPHOMAS AND MAY BE A THERAPEUTIC TARGET

Abstract

Introduction: KIR3DL2, a killer immunoglobulin-like receptor normally expressed by a subset of natural killer (NK) cells and a minority of CD4+ and CD8+ T lymphocytes, is aberrantly expressed in cutaneous T-cell lymphomas (CTCL), particularly in Sézary Syndrome (SS)1. IPH4102, a monoclonal antibody directed against KIR3DL2, demonstrated in-vitro antitumor activity and has shown beneficial clinical activity in a phase 1 dose-escalation plus expansion cohort study in relapsed advanced CTCL patients (NCT02593045)2,3. Methods: Our cohort included a total of 91 peripheral TCL (PTCL) patients. NK receptors expression was assessed by immunohistochemistry (IHC) on frozen biopsies (n = 49), and by flow-cytometry (n = 42) on peripheral blood samples (n = 12) and lymph node/tumor tissue (n = 30). Ex-vivo antibody dependent cell cytotoxicity (ADCC) assays are currently being performed on sorted primary KIR3DL2-positive PTCL cells with IPH4102. Finally, IPH4102 and gemcitabine plus oxaliplatin (GemOx), a combination chemotherapy regimen commonly used in relapsed PTCL, was studied in-vitro. Results: Overall, irrespective of the staining technique, KIR3DL2 expression was evidenced in 41/91 (45%) of PTCL patients. More precisely, KIR3DL2 was expressed on 7/20 (35%) PTCL-not otherwise specified (NOS), 9/25 (36%) angioimmunoblastic TCL (AITL), 8/14 (57%) anaplastic large-cell lymphomas (ALCL), 5/11 (45%) enteropathy-associated TCL (EATL), 5/11 (45%) NK/T-cell lymphomas, 0/2 hepatosplenic TCL and 7/8 (88%) T-cell large granular lymphocyte leukemias (T-LGL). By IHC, within all PTCL categories, > 5% of lymphoid cells were KIR3DL2-positive in 22 out of 49 cases (45 %). High expression (> 50% KIR3DL2-positive lymphoid cells) was found in 11 (22 %) patients ( figure 1A ). In addition, by flow cytometry, KIR3DL2 was expressed on tumor cells compared to isotype control in 18/42 PTCL (43%). Incubation of T-cell lymphoma cell lines with GemOx enhances baseline KIR3DL2 expression. In-vitro, IPH4102 ADCC against KIR3DL2-positive tumor T-cell lines is increased by GemOx ( figure 1B ). Keywords: monoclonal antibodies (MoAb); peripheral T-cell lymphomas (PTCL). Disclosures: Cheminant, M: Research Funding: yes. Bruneau, J: Research Funding: yes. Peri, V: Employment Leadership Position: yes. Guillot, F: Employment Leadership Position: yes. Paturel, C: Employment Leadership Position: yes. Sicard, H: Employment Leadership Position: yes. Bonnafous, C: Employment Leadership Position: yes; Stock Ownership: yes. Hermine, O: Research Funding: yes.