Development of Novel MRI-based Biomarkers for Immunotherapy of Glioma

Eric T. Ahrens, Ph.D.

Carnegie-Mellon University

Funded in September, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

back to top

New techniques reveal how T cells enter the brain and attack glioma

Investigators will develop two imaging tools for assessing the effectiveness of various experimental T cell immunotherapies being developed in mouse models as potential treatments for human brain gliomas.

Given the lack of results and serious side effects from conventional chemotherapies used to try to treat brain glioma, research that is devoted to strengthening the patient’s own immune T cells in the laboratory and then infusing them back into the patient is receiving increasing attention.  A major obstacle in developing such “immunotherapies” is the blood-brain-barrier (BBB): Scientists must design effective methods that enable the strengthened immune T cells to migrate from the body, cross the BBB and enter the brain.  If that is accomplished, the next challenge is to determine and demonstrate that the immune T cells effectively attack the tumor.  The Federal Food and Drug Administration (FDA), which must approve all drugs and biologics for interstate marketing in this country based on evidence of relative safety and efficacy, has expressed an interest in developing methods to non-invasively verify where the immune cells go immediately after being inoculated into the patient, where in the brain the cells have migrated to thereafter, and demonstrate evidence of tumor shrinkage or improved clinical outcome.

Imaging tools recently developed by these investigators, initially to study T cell migration to the pre-diabetic pancreas and now to study their migration to brain glioma, are designed to address these needs.  They removed T cells from a mouse model, labeled them in the laboratory with a perfluorocarbon (PFC) emulsion, inoculated the labeled cells back into the mice, and used MRI to track the cells’ migration. They found that this technique provides reliable estimates of the number of cells that reach a specific destination. Moreover, they also discovered that this same PFC emulsion can be used to measure the amount of oxygen present in a cell, and found that increased oxygenation is an early indication of tumor killing. They now hypothesize that this technique can be effectively used in the mouse model of glioma to quantify the number of immune T cells that migrate to the site of brain glioma and that the extent of increase oxygenation (i.e., intracellular partial pressure of oxygen) within glioma cells will correlate with the amount of T cell migration to the tumor.   They will test these hypotheses in the mouse glioma model.

Significance:  If successful in the mouse model, this new technique then would be tested in patients with glioma to see if it provides valid biomarkers for determining whether specific experimental immunotherapies are effective. 

ABSTRACT

back to top

Development of Novel MRI-based Biomarkers for Immunotherapy of Glioma

The inability to see cells in vivo following transfer is one of the greatest bottlenecks in the development of live-cell cancer immunotherapy. In this proposal we will devise tools that can be used to non-invasively detect and quantify therapeutic T cells migrating into the central nervous system (CNS). These tools will accelerate the development of effective immunotherapy against glioma. For these studies we will employ a recently devised fluorine-19 (19F) MRI cell tracking platform. In our approach, cells of interest are labeled ex vivo with a novel perfluorocarbon (PFC) emulsion composition, and the cells are introduced into the subject. Cell migration is subsequently monitored in vivo using 19F MRI. The key advantage of this method is that the 19F images are extremely selective for the labeled cells, and one can readily quantify the number of labeled cells in regions of interest. PFC cell tracking has significant potential for human translational studies. Overall, the proposal has two Specific Aims: (1a) We will devise ex vivo labeling protocols for therapeutic T cells using novel PFC-based cell labels and rigorously evaluate whether PFC labeling induces any alterations in T cell function and phenotype in vitro; (1b) we will longitudinally visualize the kinetics and quantity of labeled, therapeutic T cells migrating to CNS tumors using 19F MRI; (2a) Using ex vivo PFC-labeled glioma cells, we will longitudinally assay intracellular oxygen following implantation into the CNS and subsequent therapeutic T cell ingress into tumor regions; (2b) we will correlate the quantity of T cells found at the tumor, the mean intracellular oxygen of the glioma cells, and the degree of tumor shrinkage via conventional MRI. The Pittsburgh region has exceptional strength in cancer immunotherapy and imaging innovations. We have organized a potent research team from the region to conduct this project.

INVESTIGATOR BIOGRAPHIES

back to top
Eric T. Ahrens, Ph.D.

Eric T. Ahrens, Ph.D., is an Associate Professor in the Department of Biological Sciences at Carnegie Mellon University. He also holds an appointment in the Department of Neurobiology at the University of Pittsburgh.  Dr. Ahrens is the scientific founder and part-time Chief Scientific Officer of Celsense, Inc., a Pittsburgh-based biotechnology firm. He formerly served as a Visiting Associate and Senior Research Fellow in the Biology Department at the California Institute of Technology, as a Visiting Scientist at the IBM Watson Research Center, and as a Graduate Research Assistant at Los Alamos National Laboratory. He holds B.S., M.S., and Ph.D. degrees in physics from the University of California at Los Angeles. Dr. Ahrens’ research uses magnetic resonance imaging (MRI) to explore unique molecular, cellular, and anatomical attributes of model organisms. He is the author of more than 50 scholarly publications in biology and physics, has authored seven pending patent applications, and is an expert in cellular-molecular MRI.