Targeted Modulation of the NKG2D Axis to Trigger Anti-Leukemia NK Cell and T Cell Responses

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The natural killer group 2 member D (NKG2D) receptor / ligand axis plays a key role in the elimination of emerging tumor cells. The important roles for NKG2D in immunosurveillance of cancer have been supported in various animal models and in patients, where the risk of cancer development correlated with specific variants of the NKG2D encoding gene. NKG2D recognizes different protein ligands, which are expressed on the cell surface of virally infected cells and tumor cells and which act as danger signals. Recognition of these ligands triggers NK cell and T cell activation and results in elimination of ligand-expressing cells. During progression tumors escape this recognition through downregulation or shedding of NKG2D ligands. In AML, leukemia initiating cells have been demonstrated to lack NKG2D ligand expression thereby escaping immune recognition. In addition, in clinical studies, the expression of certain NKG2D ligands has been correlated with improved overall survival. Preliminary work based on RNA profiling suggests low NKG2D ligand expression levels in B cell leukemia and a correlation with an unfavorable treatment outcome. Therefore, novel strategies to restore / enhance NKG2D recognition of malignant cells by immune effector cells represent promising immunotherapeutic approaches to trigger antileukemia immune responses in ALL. In the proposed project we aim to develop novel antibody derivatives to specifically modulate the NKG2D axis in ALL. The cytotoxic activity of our novel agents will be tested in vitro as well as in xenograft and syngeneic mouse models of ALL. These experiments will provide proof of concept whether modulating the NKG2D axis represents a valid approach for the treatment of ALL.