The lack of effective treatments for glioblastoma (GBM) patients remains a significant health problem and highlights the need for novel and innovative approaches. The broad overall goals of this research project are to investigate mechanisms of immune evasion following active immunotherapy, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. We postulate that clinically relevant anti-tumor immunity to glioblastoma (GBM) must have two cellular components: 1) significant infiltration of tumor-specific tumor-infiltrating lymphocytes (TIL); and 2) blockade of immune-regulatory antigen presenting cell (iAPC) function within the tumor microenvironment. As such, our hypothesis is that the local cellular interactions between iAPC and T lymphocytes within the brain tumor microenvironment is a critical factor influencing the efficacy of immunotherapies in glioblastoma patients. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.
In Aim 1, we will study the mechanisms by which iAPC limit glioma-specific anti-tumor immune responses in vitro and in vivo.
In Aim 2, will we evaluate the efficacy of combining tumor lysate-pulsed DC vaccination (to induce T-cell infiltration into tumors) with immune checkpoint inhibition and other novel immunoregulatory targets (to block iAPC function) in pre-clinical syngeneic animal models of glioblastoma, and explore the use of a novel PET tracers as non-invasive imaging biomarkers of immune response.
Finally, in Aim 3, we will develop and validate predictive tumor, immunological and imaging biomarkers of response in recurrent glioblastoma patients enrolled in a Phase II clinical trial of DCVax-L +/- PD-1 blockade. These studies span the continuum of translational research in brain tumor immunotherapy, and will likely provided informative new insights for the development of new, rational immune-based strategies for brain tumor patients.