EGFRvIII targeting bi-specific T cell engager transduced macrophages trigger T cell clearance of human glioma cells
Gardell, JL1, DeGolier, KD1, Kreuser, SA1, Kelly-Sprat, KS1, Jensen, MC1, Chinn, HK1, Davis, AD1, Crane, CA1*
1Seattle Children's Research Institute, Seattle, WA
During the development of glioblastoma, a large percentage of macrophages are recruited to the tumor microenvironment. Tumor associated macrophages remain localized to the tumor site and differentiate to a phenotype that helps to support tumor growth through their secretion of anti-inflammatory cytokines and low expression of molecules associated with T cell antigen presentation and costimulation. Lentiviral transduction of macrophages allows us to manipulate macrophages so that they express a wide variety of pro-inflammatory factors. These engineered macrophages secrete proteins that rather than promoting tumor growth, support T cell killing of tumor cells and tumor clearance. In this study, we investigate the effects of macrophages that have been engineered to express the bi-specific T cell engager against the cancer antigen EGFRvIII on T cell function. GMCSF differentiated macrophages derived from human peripheral blood monocytes were transduced with a lentivirus encoding the bi-specific T cell engager. The genetically engineered macrophages were shown to induce T cell activation and degranulation, interferon gamma production, and T cell killing in the presence of EGFRvIII expressing glioma cells. The administration of bi-specific T cell engager expressing macrophages that are recruited to the tumor site may offer advantages compared to continuous intravenous administration of bi-specific T cell engager protein for the treatment of glioblastoma.