Glioblastomas are the most common primary brain tumors. Surgery, radiation, and chemotherapy improve survival but, unfortunately, these tumors remain deadly despite aggressive treatment. More effective therapies are urgently needed. Reflecting my role as a neurosurgeon and clinician-scientist, my research group focuses on three main themes:
Improving Glioma Surgery
We seek to develop and rigorously test techniques facilitating aggressive surgical resection for gliomas while maintaining or improving patient safety. These include integrating functional imaging (functional MRI, diffusion tensor imaging tractography) into image-guidance systems and intra-operative MRI, correlating this with intra-operative electrophysiological mapping, and pursuing novel strategies such as fluorescence-guided resection.
Understanding Glioblastoma Immunology
Glioblastomas suppress immune responses both locally within the tumor and systemically throughout the body. We seek to understand the cellular and molecular mechanisms underlying this immune suppression. We are testing the general hypothesis that a tightly regulated cellular network made up of glioblastoma cells, glioblastoma-infiltrating monocytes, circulating myeloid-derived suppressor cells, and regulatory T cells underlies glioblastoma-mediated immunosuppression. The roles of immunosuppressive factors expressed by many of these cells (B7-H1, TGF-ß, PGE2, IL-10) are being investigated. Model systems include in vitro interactions between cultured human glioblastoma cells (including glioma stem cells) and human leukocytes, as well as a humanized SCID/nod mouse model reconstituted with human hematopoietic stem cells and bearing human glioblastoma stem cell xenografts. As much as possible, experiments are carried out with tumor cells and leukocytes obtained from patients undergoing glioblastoma surgery at Mayo Clinic, highlighting the translational nature of these studies.
Developing Effective Glioblastoma Immunotherapies
Based on our increasing understanding of glioblastoma immunology, we seek to develop effective strategies to reverse glioblastoma-mediated immune suppression and stimulate anti-tumor immune responses. We are particularly interested in optimizing tumor vaccine timing compared to standard therapies (which can alter glioblastoma-mediated immunosuppression), manipulating dendritic cell vaccines to maximize their immunostimulatory properties, and targeting critical cell populations such and glioblastoma stem cells. In addition to studies carried out with the in vitro and in vivo models systems described above, we are fortunate to have access to the Mayo Clinic Human Cell Therapy Laboratory. This Good Manufacturing Practices (GMP) facility is capable of producing clinical grade cellular tumor vaccines. Thus, we are able to readily translate our laboratory findings back to the clinic.
We are excited by the results our research is producing but sobered by the fact that glioblastomas remain challenging tumors to address clinically. By pursuing these studies, we hope to improve the prognosis for patients facing this daunting diagnosis.