As a surgeon-scientist my research program has basic science objectives (understanding mechanisms of immunoresistance in glioma), translational objectives (vaccine therapies for glioma patients), and clinical objectives (optimizing surgical techniques and management algorithms for patients with skull base tumors, as well as developing appropriate algorithms for management of patients with rare primary CNS tumors).
Scientific and Translational Research Objectives: Glioblastoma multiforme is a terminal diagnosis, for which there is no adequate therapy. Although information regarding the genetic events that lead to the transformation is becoming increasingly available, there have been few therapeutic breakthroughs. Immunotherapy is an attractive alternative to conventional adjuvant therapy because it can specifically target malignant glial cells while preserving function of surrounding cells, including neurons. Several clinical trials of active immunotherapy for malignant glioma patients have been initiated. The failure of these clinical trials to document an objective clinical response to therapy that correlates with specific anti-glioma immunity suggests that cancer cells may be immunoresistant. My laboratory has focused on the phenomenon of immunoresistance in cancer, and how immunoresistance relates to fundamental oncogenic events. We have linked loss of the tumor suppressor PTEN in glioma to immunoresistance through post-transcriptional regulation of the immunoresistant protein B7-Homologue 1 (B7-H1), also known as programmed death ligand 1 (PD-L1) (Parsa AT et. al., Nature Medicine, 2007). This finding has provided the foundation for subsequent studies extending our results into other immunological contexts (Han S, et. al., NeuroReport, 2010) and other cancers (Crane C et. al, Oncogene, 2009). In addition we are developing novel approaches to reversing PTEN loss mediated immunoresistance (Crane C et. al., Journal of Immunotherapy, 2010). In a parallel translational effort we are seeking to optimize immunotherapy for patients with malignant glioma. I have collaborated with a biotechnology company, Antigenics Incorporated, to develop an investigator initiated clinical trial to treat recurrent glioma patients with an autologous tumor derived heat shock protein vaccine. The phase I portion of this trial has finished accrual, and we have generated some favorable initial survival data as well as compelling immunomonitoring data. A multi-center Phase II study is currently underway for recurrent glioblastoma patients as well as a single center Phase II study evaluating the vaccine in primary glioblastoma patients treated with chemotherapy after radiation.
Clinical Research Objectives: The management of rare CNS tumors, including skull base tumors, is confounded by the lack of consensus data on optimal surgical approach and post-operative adjuvant treatment. As a step towards understanding what issues are important, my clinical research group has focused on completing comprehensive meta-analysis of the published literature on specific tumor types with strict inclusion criteria. These studies have generated several peer-reviewed publications that have subsequently formed the basis for retrospective reviews of our patients here at UCSF. A series of studies published on gliosarcoma by my group highlight the approach of analyzing the literature then subsequently analyzing our own series of patients (Han S. et al. Journal of Neuro-Oncology, 2009, Han S et. al. Journal of Neurosurgery 2010, Han S et. al Cancer 2010). Gliosarcoma is a rare tumor type often grouped together with glioblastoma when considering enrollment into clinical trials. Our work, first using the existing data and then our own patients, supports the premise that gliosarcoma and glioblastoma are clinically distinct entities. Another example of our approach can be found in a series of papers on vestibular schwannomas also known as acoustic neuroma and skull base meningiomas. In these peer-reviewed publications (over 20 total in the last few years) we have carefully interrogated the reported outcomes for various management paradigms, and then subsequently queried our own prospectively collected database to further explore these management paradigms. These clinical studies have been highly cited and are an important step towards developing consensus on management of these rare tumors. Ultimately my goal is to form a consortium of investigators at various institutions to initiate prospective studies accruing data on rare CNS tumors, and skull base tumors in particular.
Current Research Projects
Immune response in a V12Ha-ras transgenic model of glioma
Glial cells are integrally involved in maintaining functional integrity of the nervous system. Neurological disorders can result when extra-neuronal cells such as glia transform into malignant tumors. Although information regarding the genetic events that lead to this transformation is becoming increasingly available, there have been few therapeutic breakthroughs. Immunotherapy is an attractive alternative to conventional adjuvant therapy because it can specifically target malignant glial cells while preserving function of surrounding cells, including neurons. Several clinical trials of active immunotherapy for malignant glioma patients have been initiated. The failure of these clinical trials to document an objective response to therapy that correlates with specific anti-glioma immunity is concerning. To date, all clinical studies of anti-glioma immunotherapy have been based upon pre-clinical data using models that do not have a tumor specific antigen. The availability of a recently developed V12Ha-ras transgenic model of glioma provides a unique opportunity to ask fundamental questions regarding antigen specific immunity against transformed glia. Using this model we are testing the hypothesis that local anti-tumor immunity inversely correlates with intracranial glial tumor burden (K08 NS046671).
Immunotherapy for Glioma
In a parallel translational effort we are seeking to optimize immunotherapy for patients with malignant glioma. Vaccine therapies designed to provoke a cellular immune response may depend upon both tumor specific CD8+ T-cells and cytokine-stimulated natural killer (NK) cells. Tumor-specific cytotolytic CD8+ T-cells (CTLs) can undergo anergy or apoptosis in response to proteins expressed by gliomas, while NK cells may be rendered ineffective by proteins that confer resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated killing. B7-Homologue 1 (B7-H1), also known as programmed death ligand 1 (PD-L1), is a recently discovered cell surface protein that inhibits anti-tumor immunity by inducing T-cell apoptosis, impairing cytokine production, and diminishing the cytotoxicity of activated T-cells. It can be considered an "offensive" protein that actively changes the tumor micro-environment by reducing the effectiveness of tumor-specific T-cells. FADD-containing inhibitor of caspase-8 cleavage short protein (FLIPS) may confer resistance to TRAIL-mediated NK cell killing. It can be considered a "defensive" protein that may passively change the tumor micro-environment by reducing susceptibility of a glioma to NK cell killing. We believe that tumor specific proteins such as B7-H1 and FLIPS can limit the efficacy of glioma immunotherapy. We are currently testing the hypothesis that activation of the PI(3)K/Akt/mTOR pathway in glioma suppresses innate (NK cell) and adaptive (T-cell) anti-glioma immune responses (2 P50 CA097257-06).
In an associated therapeutic effort I have collaborated with a biotechnology company, Antigenics Incorporated, to develop an investigator initiated clinical trial to treat recurrent glioma patients with an autologous tumor derived heat shock protein vaccine (NCI SPORE Supplement for translational research). The phase I portion of this trial is completing accrual, and we have generated some remarkable anectdotal efficacy data as well as compelling immunomonitoring data.