IPH2101 contracts and detunes NK-cells in vivo

Purpose: Immune checkpoint inhibitors have recently revolutionized cancer immunotherapy. Based on data showing KIR-ligand mismatched NK-cells reduce the risk of leukemia and multiple myeloma (MM) relapse following allogeneic hematopoietic stem cell transplantation, investigators have developed a checkpoint inhibition antibody that blocks KIR on NK-cells. Although in vitro studies suggest the KIR2D-specific antibody IPH2101 induces KIR-ligand mismatched tumor killing by NK-cells, our single-arm phase II clinical trial in patients with smoldering MM was prematurely terminated due to lack of clinical efficacy. This study aimed at unveiling the underlying mechanisms behind lack of clinical efficacy. Experimental Design: Treatment-naïve patients received an intravenous infusion of 1 mg/kg IPH2101 every other month for up to a year. Peripheral blood was collected at baseline and twenty-four hours after first infusion, followed by weekly samples for the first month and monthly samples thereafter. NK-cell phenotype and function was analyzed using high-resolution flow cytometry. Results: Unexpectedly, infusion of IPH2101 resulted in rapid reduction in both NK-cell responsiveness and KIR2D expression on the NK-cell surface. In vitro assays revealed KIR2D molecules are removed from the surface of IPH2101-treated NK-cells by trogocytosis, with reductions in NK-cell function directly correlating with loss of free KIR2D surface molecules. Although IPH2101 marginally augmented the anti-myeloma cytotoxicity of remaining KIR2Ddull patient NK-cells, the overall response was diminished by significant contraction and reduced function of KIR2D-expressing NK-cells. Conclusions: These data raise concerns that the unexpected biological events reported in this study could compromise antibody-based strategies designed at augmenting NK-cell tumor killing via checkpoint inhibition.

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