ABSTRACT

Lirilumab is a fully human monoclonal antibody designed to block killer inhibitory receptors (KIR), which are major immune checkpoints involved in the regulation of NK cell-mediated killing of HLA-I-expressing tumors. EFFIKIR is a multicenter randomized double-blind 3-arm placebo-controlled phase II trial with lirilumab as single-agent as maintenance therapy of elderly patients with AML in first complete remission ( NCT01687387 ). Two dose schedules led to either continuous or intermittent KIR occupancy. 153 patients were randomized and 152 patients were treated after 3+7 induction therapy. The median follow-up was 36.6 months. Lirilumab was well tolerated, with no significant hematological toxicity. The median LFS were 17.6, 6.7 and 13.9 months in the 0.1mg/kg arm, 1mg/kg arm and placebo arm, respectively. An excess in early relapse led to early termination of treatment in the 1mg/kg arm. Extensive analysis of immune cell fate following KIR blockade evidenced a decrease of KIR + NK cell absolute counts following KIR blockade, associated with a decrease of Bcl-2. Lirilumab also bound antigen-experienced CD8 + T cells, and induced a transient decrease of CD69 expression. Besides, lirilumab bound vδ2 + γδT cells with a high cytotoxic potential, and induced a decrease of DNAM-1 and Bcl-2, the latter being associated with a decrease of KIR + γδT cell, and with a drastic reduction of time to relapse. Overall, the potentially deleterious effects on immune effectors may have resulted in the impairment of immune surveillance associated with an unexpected high rate of early relapse in the group of patients exposed to prolonged full KIR blockade.

KEY POINTS

Prolonged full KIR blockade leads to potentially deleterious effects on NK cells, CD8 + T cells and vδ2 + γδT cells Combined inhibitory effects of KIR blockade may have resulted in the impairment of immunosurveillance associated with high rate of relapse