A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies.

Norbert Vey,Jaafar Bennouna,Anthony Gonçalves,Robert Zerbib,Florence Broussais,Delphine Marie,Lionel Karlin,Carine Paturel,Jérôme Rey,Sophie Sadot-Lebouvier,Aude Charbonnier,Gilles Salles,Pascale André,Dominique Berton-Rigaud

doi:10.18632/oncotarget.24832

Abstract

PurposeAnti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers.Experimental designThirty-seven patients with hematological malignancies (n = 22) or solid tumors (n = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 (n = 9) or 3 mg/kg (n = 8).ResultsNo dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D-positive NK cells.ConclusionsThis phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR.

Highlights

Antibodies that block the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed death-1/programmed death-ligand-1 (PD1/PD-L-1) immune checkpoints have highlighted the potential of strategies that target tumor-induced inhibition of T cells to induce clinically relevant tumor control [1].many patients fail to respond optimally to PD-1 and cytotoxic T-lymphocyteassociated protein (CTLA)-4 blockers, maybe due to lack of potential immunological targets
We evaluated the safety of the anti-KIR2D monoclonal antibodies (mAbs) lirilumab in patients with various cancers
The most frequent lirilumabrelated adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate

Summary

Introduction

Antibodies that block the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed death-1/programmed death-ligand-1 (PD1/PD-L-1) immune checkpoints have highlighted the potential of strategies that target tumor-induced inhibition of T cells to induce clinically relevant tumor control [1].many patients fail to respond optimally to PD-1 and CTLA-4 blockers, maybe due to lack of potential immunological targets. Antibodies that block the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed death-1/programmed death-ligand-1 (PD1/PD-L-1) immune checkpoints have highlighted the potential of strategies that target tumor-induced inhibition of T cells to induce clinically relevant tumor control [1]. There is a need for new drugs that block alternative immune checkpoint receptors. The mobilization of additional types of immune effector cells, such as natural killer (NK) cells, which can cooperate with T cells to produce coordinated antitumor responses, may be a promising therapeutic strategy. NK cells are critical effectors of the innate immune system; they are regulated by a balance of signaling from activating and inhibitory receptors and possess potent anticancer effects in a variety of tumor models [2, 3]. NK cell number and function correlate with relapse-free survival in acute myeloid leukemia (AML) [4, 5]

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