O3.2 - Phase I and dose ranging, phase II studies with IPH2201, a humanized monoclonal antibody targeting HLA-E receptor CD94/NKG2A

Abstract

ABSTRACT There has been a recent resurgence of interest in immunotherapy, particularly in the domain of immune checkpoint inhibitors. Ipilimumab and pembrolizumab have been approved for the treatment of melanoma; these 2 agents and several others are being investigated in multiple tumor types and have shown substantial activity including in hematologic malignancies. IPH2201 is a first-in-class anti-NKG2A antibody (Innate Pharma (IPH)). NKG2A is an inhibitory checkpoint receptor that controls both innate immunity (via NK cells) as well as adaptive immunity (via cytotoxic T cells). NK and cytotoxic T cells are inhibited when NKG2A binds to its ligand, HLA-E, expressed on tumor cells. Hence, expression of HLA-E can protect cancer cells from lysis by NKG2A+ NK and T cells. IPH2201 binds with high affinity to NKG2A and reverses inhibitory signaling in NK and CD8+ T cells resulting in cytotoxic effects. A double-blind placebo-controlled phase I study of IPH2201 has been conducted in 92 patients. No dose limiting toxicity was observed; a maximum tolerated dose was not reached. Doses in the range of 0.25–10 mg/kg given either subcutaneously (sc) or intravenously (iv) achieved full NKG2A receptor occupancy on peripheral blood cells for > 2 weeks. Tumour types known to express HLA-E, including chronic lymphocytic leukemia, head and neck cancer and ovarian cancer (OVCA) are targeted for clinical trials. Ovarian cancer is an attractive target as HLA-E is up-regulated in ∼ 80% of patients, HLA-E appears to be prognostic, and CA125 may inhibit cytotoxic responses of NK cells. NCIC CTG is conducting a phase I study of IPH2201 in previously treated patients with OVCA. In part one, 18 patients will be randomized to one of three iv doses of IPH2201 (1-4-10 mg/kg). In the expansion part, 20 platinum sensitive or resistant patients will be enrolled. Safety, response (RECIST 1.1 and modified Immunotherapy criteria), PK and pharmacodynamic studies are planned, including serial tissue acquisition, flow cytometry for NKG2A receptor occupancy and circulating tumor cell (CTC) estimation.