Browsing by Subject "T-cell"

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    The Divergent Role of Co-receptors and Cytokines in the Immune Response to Cancer and Self
    (2020-08) Tucker, Christopher
    The mammalian immune system has evolved over millennia to respond to countless biologic factors and environmental cues. This exquisite system has been shaped over time, to destroy hostile invaders all while sparing healthy surrounding tissue. The immune system is vital to survival, a fact that is readily apparent when immune components are mutated in human disease or mouse models. When immune components are lost, this balance can be distorted in both directions. Alterations to pro-inflammatory molecules, such as Tumor Necrosis Factor alpha (TNFα) can increase infection and cancer risk. Conversely, mutations in immunoregulatory pathways such as programmed death-1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been associated with increased autoimmune disease incidence. This balance is uniquely apparent in the PD-1 pathway and CTLA4 pathways. Blockade of the PD-1 pathway can elicit potent anti-tumor responses, as evidenced by monoclonal antibody therapy Nivolumab and Pembrolizumab response rates, but also can unleash off-tissue pathology such as type one diabetes (T1D). T1D in these cancer patients is rapid and severe. This is perhaps not surprising, as Non Obese Diabetic (NOD) mice treated with anti-PD-1 or anti-PD-L1 therapy rapidly succumb to fulminant T1D. In common, CTLA4 blockade has been shown to halt tumor growth and even cure patients of metastatic cancer, however it has also unleashed potent autoimmune responses in the gut, brain, heart and eyes. Being able to better dissect these pathways, determine who will respond poorly to therapy and how these therapies can be maximized for tumor destruction, are key questions to be answered by the field of immunology. Complementary to the idea of blocking an inhibitory signal, positive signals are also used to invigorate the immune system. OX40, a TNF receptor family member, has been shown to be integral in provide co-stimulation to effector and naïve T-cells, and agonism through this receptor can cause potent anti-tumor effects. Interconnected and also important, the cytokine IL-12 has been shown to induce profound changes in T-cells, driving cytolytic T-cell programming, higher cytokine production, better tumor trafficking, proliferation and survival in the tumor environment while preventing tumor induced T-cell exhaustion. Like PD-1 and CTLA4, both OX40 and IL-12 are associated with their own unique set of autoimmune conditions. The focus of this chapter and this thesis as whole will be on these two immunoregulatory pathways, PD-1 and CTLA-4 as well as two immunostimulatory pathways OX40 and IL-12 and their relative importance in autoimmunity and cancer immunity.
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    Immunological benefits of a novel polycaprolactone-polyorthoester-based therapeutic vaccine in a mouse model of glioma
    (2014-08) Grinnen, Karen Lynn
    Cancer immunotherapy has led to significant improvement in the survival of patients with previously untreatable malignancies. The use of therapeutic vaccines is a promising form of immunotherapy, but their efficacy remains ambiguous. Much of the difficulty in identifying the optimal formulation and delivery is related to the complicated nature of the immune response, where it is uncertain which aspects would be most effective in destroying cancer cells. In this thesis, a novel polymeric delivery system, involving poly (caprolactone)-co-poly (ortho ester) [PCL-POE], was used to deliver tumor antigens and adjuvants in a controlled manner. We hypothesized that persistent release of tumor antigens from the biodegradable polymer would result in an increase in the number and persistence of anti-tumor lymphocytes in the effector state. To test this hypothesis, vaccines were administered to mice and the time dependent immunological response was evaluated. The polymeric delivery system resulted in an in vitro release profile characterized by a burst release of both antigen and adjuvant followed, in both cases, by a much slower phase of release. We also observed that the slow release provided by the PCL-POE polymer stimulated prolonged maturation of dendritic cells, activation and persistence of anti-OVA antibodies and antigen-specific T cells following a single vaccination. The vaccine system was also tested in a mouse model of glioblastoma multiforme (GBM). We observed a significant, potentially translatable increase in overall survival.