Average survival times for glioblastoma patients remain around 15 months because of relatively few effective treatments. CD11b+ Tumor-associated myeloid cells, can account for up to 40% of the tumor mass, are well known to suppress anti-tumor immunity, and directly promote tumor growth. While significant advances have been made in the development of TAMC-targeted therapies, analysis of TAMCs requires analysis of surgically resected tumor tissue. In this R21 application we propose that development of a novel tracer, Cu-64 labeled antibody fragments, which will allow for non-invasive PET imaging of TAMCs in glioblastomas. We will therefore, test our novel hypothesis that Cu-64-labeled monobodies or diabodies derived from the m1/70 hybridoma will enable quantification TAMC infiltration into the tumor and monitoring of TAMC-targeted immunotherapies. We will first generate and test the sensitivity of our antibody fragments following injections of varying concentrations of CD11b+ mouse spleenocytes from C57BL/6j mice into CD11b-knockout C57BL/6j- background syngeneic glioma-bearing mice (Aim 1). We will then demonstrate that our novel antibody fragments can be used to monitor TAMC-targeted therapies including anti-Gr1-antibody, Celecoxib, or a CSF-1R inhibitor in the GL261 syngeneic glioma model, and a de novo glioma model (AIM 2). As the m1/70 clone can recognize both human and mouse CD11b, we believe that our preclinical studies can lead to quick translation of our findings into TAMC-targeted clinical trials in patients with glioblastoma, or in patients with other neuroinflammatory disorders. !
Glioblastoma multiforme (GBM) is a tumor of the brain with few effective therapies. We are developing methods of non-invasive diagnostic imaging in experimental animal models of some of the cells within GBM that are responsible for therapeutic failure. Successful completion of the project will lead to the introduction of new tracers to direct the new therapies for this group of cells in patients with GBM.
