Glioblastoma (GBM) is an extremely aggressive brain cancer, with fewer than 5% of patients surviving to 5 years after diagnosis. The GBM microenvironment fuels its pathogenesis through the expression of CD155, which drives inhibition of NK cell effector functions via its ligand TIGIT, and the hypoxia-driven generation of adenosine from ectoenzyme CD73. Adenosine, in turns, impairs the anti-tumor function of natural killer (NK) cells. As a result, GBM immunotherapies with adoptively-transferred NK cells can be subject to severe immunosuppression. In order to improve the treatment of GBM, this proposal describes the development of a novel immunotherapy with NK cells engineered to co-target, in a responsive manner, the inhibitory functions of TIGIT and CD73. We propose to do so by engaging synthetic notch signaling to usurp TIGIT binding on NK cells and trigger the local release of CD73 antibody fragments. We will characterize the anti-tumor function and GBM infiltration of these cells in orthotopic GBM xenografts and make a case for the use of these allogeneic engineered cells as a safe, powerful immunotherapeutic modality. The highly translational project proposes to develop curative new immunotherapies for GBM which have the potential to be be translated into effective clinical treatments in humans.
The dysfunction of natural killer (NK) cells in glioblastoma (GBM) occurs due deep hypoxic cores which create immunosuppressive niches promoting the accumulation of extracellular adenosine, alongside the expression of inhibitory receptors on NK cells, including TIGIT. These inhibitory signaling mechanisms impair effector function and anti-tumor immunity of NK cells. The goal of this proposal is to develop and characterize a novel immunotherapy for GBM that utilizes engineered NK cells which can usurp TIGIT binding in combination with the local release of CD73 in a responsive manner using a novel ?sensing-and-response? synthetic Notch signaling construct by mediating superior GBM cytolysis toward clinical translation in humans.
