Research Interests

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 measure the immune response evoked by vaccination.  We use this information to design more effective therapy.

See publications for more informtation on our research program.