Malignant gliomas are the most common primary brain tumors and have a very poor prognosis (12–18 months with current treatments). Since 1997, the Wheeler Laboratory has been examining whether cellular vaccines against gliomas effectively generate anti-tumor responses and further extend survival in grades 3 and 4 glioma patients. Current trial results indicate mean survival of 36 months after vaccination in grade 4 glioma patients (glioblastoma multiforme), and interim results from a placebo-controlled, multicenter phase II vaccine trial were reported in 2014.
The Wheeler Lab is interested in new ways to improve glioma vaccines and in understanding how gliomas resist destruction by otherwise effective killer immune cells. We are particularly focused on the role of certain sugars attached to immune receptors, which dramatically alter their reactivity to self-protein antigens. We have found that removing one sugar (sialic acid) from the T cell coreceptor, CD8, improves their responsiveness to tumor proteins, and can be combined with anti-tumor T cell activity to prolong survival in glioma hosts. The Wheeler Laboratory is now testing whether combining sialic acid removal with cellular vaccination can further increase vaccine benefits.
Another aspect of gliomas being studied in the Wheeler Lab is how they change after immunotherapy. We previously found that gliomas increase in drug sensitivity after vaccination, and also change their expression of many genes involved in progenitor cell function and differentiation. We now know that tumor differentiation genes change in a very defined way, and determining the immune and tumor machinery controlling these changes may allow us to combine vaccination with targeted drug treatments to further improve benefits.
Alzheimer's disease (AD) is the leading cause of age-related dementia; however, other than aging itself, the cause for more than 99 percent of cases is not clear. Certain immune defects commonly occur with aging, and the Wheeler Laboratory has developed a novel experimental system to examine how a very common aspect of immune aging (age-related CD8 T cell clonal expansion, or TCE) affects brain disorders including AD. Preliminary data indicate that CD8 TCEs induce an array of neuropathological changes associated with AD, and that lytic and proinflammatory functions of T cells distinctly alter this process. This is currently being verified in AD patients and may lead to the development of novel immune targets for AD prevention and treatment.
Aged T cells (left) and amyloid deposition (right) within brain
Neural Development and CD8 T Cells
A limited number of new neurons can be produced in the adult brain to contribute to tissue homeostasis and repair, and this process (adult neurogenesis) tends to decrease with aging. Multiple T cell products are known to alter adult neurogenesis. Using our novel experimental system, the Wheeler Lab is studying whether aging T cells and their proinflammatory products cause the age-related decrease in adult neurogenesis. The Wheeler Laboratory is also interested in how non-aged T cells impact the brain. We are examining how a certain type of newly produced T cell, which is missing in a genetically engineered strain of rodents, appears to improve neurogenesis and protect against acquiring gender-biased behavioral symptoms of autism spectrum disorder (ASD), including repetitive activity, aversion to novelty and aberrant socialization without learning deficiency in females, and overt hyperactivity and delayed learning in males.
|New neurons in T cell-deficient brain|