NEIM-01 IMMUNOSUPPRESSION IN THE GLIOMA MICROENVIRONMENT: USING PET IMAGING TO HIGHLIGHT THE PRESENCE OF TIGIT

Abstract

Abstract Malignant gliomas are one of the drivers of brain tumor patient mortality as these tumors respond poorly to conventional therapies and are known to grow aggressively. Many clinical trials have evaluated the efficacy of novel immuno-therapeutics targeted to gliomas; however, these trials have largely been unsuccessful. It is believed that one of the primary reasons immunotherapies have been unsuccessful in gliomas is due to the highly immunosuppressive nature of the tumor microenvironment. T cell immunoreceptor with Ig and ITIM domain (TIGIT) is an IC receptor that is expressed on activated T cells, Natural Killer (NK) cells, and Regulatory T cells (Tregs). It has been well established that TIGIT has a primary role in down-regulating T cell and NK cell function and can serve as an inhibitor of anti-tumor immune responses. Our laboratory and others have shown that anti-TIGIT therapy may be promising for the treatment of adult gliomas via glioma patient transcriptomic data and preclinical models. In this study, our team created a radiolabeled tracer (referred to as 89Zr-DFO-TIGIT) that bound TIGIT antigen with moderate immunoreactivity (57.7% ± 3.5%). Binding affinity was determined by performing bead-based immunoreactivity assays. To create 89Zr-DFO-TIGIT, a TIGIT monoclonal antibody was conjugated to the metal chelator DFO and radiolabeled with 89Zr. Following tracer preparation, glioma-bearing mice (GL261 cell line) were injected with 89Zr-DFO-TIGIT allowing for the visualization of TIGIT in the tumor microenvironment. PET imaging analyses revealed tracer-to-tumor uptake that increased from day one to day eight while biodistribution studies confirmed that there were significantly higher amounts of 89Zr-DFO-TIGIT detected in the glioma-bearing mouse brain hemisphere compared to the non-tumor bearing hemisphere. We now intend to evaluate 89Zr-DFO-TIGIT in a glioma-bearing large animal model to determine if this method demonstrates similar efficacy in visualizing immunosuppression in the tumor microenvironment before proceeding to clinical studies.