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Home > Neurosurgery Research > BTRC > Parsa Laboratory  
Parsa Laboratory
Principal Investigator: Andrew T. Parsa MD, PhD
As a surgeon-scientist, my research program has basic science objectives (immunoresistance in glioma and antigen specific modeling of glioma), translational objectives (vaccine therapies for glioma), and surgical objectives (optimizing techniques and innovations for complex skull base and intramedullary spinal tumor surgery).
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).
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.
Current Parsa Lab Members
Jeff Barry
Kristine Cachola
Courtney Crane, PhD
Tshilumba Kabongo
Joseph Murray
Michael Sughrue, MD
James Waldron, MD
Isaac Yang, MD
Parsa Lab Alumni
Ian Parney, MD, PhD
Robert Brownell
John Chi, MD, MPH
Ryan Gallagher
Janet Lee, MD, MPH
Lashaun and Lashay Mclinton
Jessica Oehlke
Osarhiemen Omwanghe
David Wilson
UCSF UCSF Medical Center UCSF School of Medicine