John Ohlfest, Ph.D.
Assistant Professor, Department of Neurosurgery
Director, Gene Therapy Program, Department of Neurosurgery
Director, Gene and Stem Cell Core Facility
The Ohlfest lab is focused on understanding the mechanisms of brain tumorogenesis and immune evasion, and using this information to improve therapeutic outcome. There are a several projects ongoing that all relate to the central goal.
Brain Tumor Immunotherapy: Although select patients appear to benefit from immunotherapy, there is considerable debate about the optimal way to maximize the effectiveness of immunotherapy. Our research aims to improve the efficacy of tumor vaccines using several different mouse models of glioma, an aggressive brain tumor. We are systematically optimizing each step of the immune response that occurs following vaccination from the innate response at the vaccination site to the effector response in the brain. There are several ongoing projects in this area.
1) Influence of oxygen tension on tumor cell immunogenicity
2) Toll-like receptor agonists as vaccine adjuvants
3) Optimizing the priming of tumor-reactive T cells in the lymph nodes
4) Understanding factors that influence lymphocyte trafficking into the brain
5) Understanding and overcoming immune suppression at the tumor site
6) Requirements for antibody and NK cell response in vaccination
Requirements for Tumor Renewal and Progression: Glioblastoma is difficult to cure by surgery because glioma cells migrate centimeters away from the main tumor mass and self-renew to repopulate the tumor. We have identified CD44, a cell surface receptor for hyaluronic acid, as playing a key role in glioma cell invasion and self-renewal. Using CD44+/+ and CD44-/- mice, we are interrogating the role CD44 plays in the tumor recurrence, resistance to chemotherapy, and evading the immune response. This project is made possible due to the novel spontaneous glioma model we developed that can be induced in any mouse strain (Cancer Res. 2009 Jan 15;69(2):431-9.).
Drug Delivery: The blood brain barrier (BBB) restricts the influx of drugs into normal brain structures where glioma cells typically infiltrate. The BBB has a mechanical (size exclusion) and active mechanism (ATP-dependent drug transporters) to exclude drugs and antibodies from entrance. We have several projects ongoing in this area will the goal of increasing the efficacy of drugs to treat tumors directly, or by delivering drugs overcome immune suppression at the tumor site.
1) Pharmacologic inhibition of drug efflux transport at BBB and tumor cell barriers
2) Convection enhanced delivery (CED) by neurosurgical intervention to bypass the BBB by placing catheters in the brain directly
3) Improve catheter design for CED
4) Chemotherapy conditioning to deplete myeloid derived suppressor cells and regulatory T cells
Comparative Oncology: While mouse models of brain cancer provide us with important information, they are limited in their ability to predict human responses. Therefore we have initiated a canine brain tumor clinical trials program. We currently offer several clinical trials to pet owners that are faced with the diagnosis of a brain tumor in their dog. These treatments include anti-tumor vaccines, chemotherapy, gene therapy, and convection enhanced delivery. Moreover, we typically perform surgery to removal as much of the tumor as possible; this maximizes the benefit for the dog and mimics the human clinical situation. Because these canine tumors are naturally arising and can be treated with human-scale doses, the results have great relevance to human medicine. This research program plays an instrumental role in our clinical trial design in humans.
Clinical Research: We are actively involved in clinical trials. Our lab has developed immunotherapy interventions that will be tested in brain tumor patients. In addition to developing the treatment, we also conduct immune monitoring to me
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Olin MR, Andersen BM, Litterman AJ, Grogan PT, Sarver AL, Robertson PT, Liang X, Chen W, Parney IF, Hunt MA, Blazar BR, Ohlfest JR. Oxygen is a master regulator of the immunogenicity of primary human glioma cells. Cancer Res. 2011 Nov 1;71(21):6583-9. Epub 2011 Sep 9.
Waldron NN, Kaufman DS, Oh S, Inde Z, Hexum MK, Ohlfest JR, Vallera DA. Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer. Mol Cancer Ther. 2011 Oct;10(10):1829-38. Epub 2011 Aug 23.
Agarwal S, Sane R, Oberoi R, Ohlfest JR, Elmquist WF. Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain. Expert Rev Mol Med. 2011 May 13;13:e17.
Xiong Z, Ohlfest JR. Topical imiquimod has therapeutic and immunomodulatory effects against intracranial tumors. J Immunother. 2011 Apr;34(3):264-9.
Oh S, Tsai AK, Ohlfest JR, Panoskaltsis-Mortari A, Vallera DA. Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. J Neurosurg. 2011 Jun;114(6):1662-71. Epub 2011 Feb 4.
Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. J Pharmacol Exp Ther. 2011 Jan;336(1):223-33. Epub 2010 Oct 15.
Olin MR, Andersen BM, Zellmer DM, Grogan PT, Popescu FE, Xiong Z, Forster CL, Seiler C, SantaCruz KS, Chen W, Blazar BR, Ohlfest JR. Superior efficacy of tumor cell vaccines grown in physiologic oxygen. Clin Cancer Res. 2010 Oct 1;16(19):4800-8. Epub 2010 Sep 21.
Tsai AK, Oh S, Chen H, Shu Y, Ohlfest JR, Vallera DA. A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature. J Neurooncol. 2011 Jun;103(2):255-66. Epub 2010 Sep 10.
Bodempudi V, Ohlfest JR, Terai K, Zamora EA, Vogel RI, Gupta K, Hebbel RP, Dudek AZ. Blood outgrowth endothelial cell-based systemic delivery of antiangiogenic gene therapy for solid tumors. Cancer Gene Ther. 2010 Dec;17(12):855-63. Epub 2010 Aug 20.
Swaminathan SK, Olin MR, Forster CL, Cruz KS, Panyam J, Ohlfest JR. Identification of a novel monoclonal antibody recognizing CD133. J Immunol Methods. 2010 Sep 30;361(1-2):110-5. Epub 2010 Jul 30.
Agarwal S, Sane R, Gallardo JL, Ohlfest JR, Elmquist WF. Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. J Pharmacol Exp Ther. 2010 Jul;334(1):147-55. Epub 2010 Apr 26.
Pluhar GE, Grogan PT, Seiler C, Goulart M, Santacruz KS, Carlson C, Chen W, Olin MR, Lowenstein PR, Castro MG, Haines SJ, Ohlfest JR. Anti-tumor immune response correlates with neurological symptoms in a dog with spontaneous astrocytoma treated by gene and vaccine therapy. Vaccine. 2010 Apr 26;28(19):3371-8. Epub 2010 Mar 1.
Current Graduate Students:
Brian Anderson (Neuroscience, University of Minnesota).
Derek Dziobek (Neuroscience, University of Minnesota).
Former Graduate Students:
Stacy Decker (Neuroscience, University of Minnesota).