Grand Rounds is a long standing lecture series here at New York Presbyterian Hospital for physicians, residents and medical students. The series usually focuses on clinical developments but last month, attendees were able to learn about the latest research being done at the Bartoli Brain Tumor Lab.
Under the direction of Dr. Jefferey Bruce, the lab has a large team of researchers who focus on three main areas of interest: the mechanism by which tumors begin, new treatments for glial cell-derived tumors, and the immune response to brain tumors.
“Despite ongoing improvement of surgical approaches, glioblastoma multiforme remains the most aggressive and prognostically devastating brain tumor,” says Dr. Sims. “The cells of this tumor remain stubbornly persistent despite varied attempts at chemotherapy and radiation treatment.”
One of the reasons this tumor is so hard to treat is that GBM tumors are known to suppress the body’s own immune response to fight the disease. Specifically, Dr. Sims is looking to see why T cells that can target the tumor behave the way they do.
“If the immune system is our defense department, T cells are the troops,” explains, Dr. Sims. “They are there to directly protect the body from external attacks (i.e. pathogens) as well as maintain order against internal uprisings (i.e. cancer).” This requires that the T cells recognize and attack specific antigens, such as viral proteins or mutated versions of proteins that occur in cancer. They do this using a part of the T cell called the T cell receptor.
“Within a single person, the gene that encodes the T cell receptor is diversified at the DNA level, so that each T cell expresses a receptor that recognizes something different,” says Dr. Sims. “In glioblastoma and many other cancers, we know that even though there should be a population of T cells that BOTH recognize the tumor AND attack hard enough to make a dent in it, for some reason, that immune reaction isn’t effective. This could be because T cells that recognize the tumor are there but aren’t fired up enough; it could be because they are there, they are fighting hard, but other cells in the tumor are shooting them down; and/or — and this would be synergistic — by the late stages of glioblastoma there aren’t enough T cells around that can recognize the tumor.”
Dr. Sims and her colleagues collected blood and tumor samples from patients who had their tumors removed at New York Presbyterian Hospital. In so doing, they have started a TCR library that shows changes in immunity surrounding tumors from low grade to high grade. Using sequencing, we can compare the T cells in the tumor tissue, to the broader population of T cells in the body. Sims says they eventually want to include samples from patients undergoing therapeutic and vaccine trials.
“How this undermining of T cell efficacy evolves during tumor progression is more poorly understood in glioma than in many other cancers, for a lot of reasons,” says Dr. Sims. “But if we can figure out how it happens, the state of the T cell population could prove to be diagnostic of tumor development. If we can figure out how to perturb that process at an early stage — how to boost our attack potential, how to protect the tumor-specific troops from being neutralized in the tumor interior, how to resuscitate an exhausted or depleted T cell force — we’d be looking at therapies that could not just improve that stubborn and terribly short GBM prognosis, but could greatly lengthen or even prevent glioma progression, by enlisting our own natural defenses.”
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