"For nearly forty years, we have recognized the tremendous capacity for glioblastoma to not simply evade, but to systematically hunt down and damage patient T cells, which might otherwise foster anti-tumor immunity. This award will permit us to further elucidate and reverse the tumor's newly discovered mechanisms for sequestering away T cells so that their number and function may be restored."
- Dr. Peter Fecci
- Associate Professor, Neurosurgery, Duke University School of Medicine
- Assistant Professor, Pathology
- Director, Brain Tumor Immunotherapy Program
- Neurosurgeon, Duke Health
About DSA-Funded Research
Immune-based therapies for glioblastoma (GBM) are hampered by reductions in the number and function of patient blood cells called T cells. For decades, it has remained a mystery as to the fate of those T cells that go missing. Our mouse models of GBM reveal that T cells disappear not only from blood, but also from lymph nodes, spleens, and thymus, all of which shrink in size. However, while T cells disappear from these sites, they instead appear in dramatically increased numbers in the bone marrow of GBM-bearing mice. The same proves true in GBM patients, and our studies demonstrate 30% reductions in spleen size, AIDS-level CD4 T cell counts, and marked bone marrow T cell accumulation. In mice, we have detected lower levels of a receptor, termed S1P1 levels, on the T cell surface, which further studies indicate may be to blame. TGF B secreted by GBMs, may be the cause of the low T cell S1P1 levels, with their resultant exile to the marrow. Importantly, when we employ drugs that force the release of T cells from the bone marrow, we witness enhanced survival in mice with GBM. Furthermore, when these drugs are combined with immunotherapies that activate the released T cells, we observe long-term survivors that universally reject any subsequent tumors implanted within the brain. We propose to further characterize the T cell sequestration, delineate the causes, and devise appropriate means for releasing them, with the ultimate goal of creating a new and effective mode of brain cancer therapy.
"With regard to the bone marrow T cell sequestration, the data and the story are compelling, the rationale for his studies thoughtful, and his commitment to proper scientific design and reporting are inspiring. These are tremendous findings, with implications for glioblastoma and immunology more broadly."
Darell D. Bigner, M.D., Ph.D.
The Preston Robert Tisch Brain Tumor Center at Duke
"I share the opinion of all those who encountered Peter over the course of his training and career thus far: this is one of future major contributors to the study and treatment of brain tumors. I cannot imagine him as anything but a leader in the field. Certainly he possesses the talent, dedication, and personality to create, disseminate, and motivate the successes that will breed much needed progress in neuro-oncology."
Robert L. Martuza, M.D.
Harvard Medical School and Massachusetts General Hospital