<p>Glioblastoma multiforme (GBM) is a common and lethal type of brain cancer, with a very poor prognosis. Current therapy consisting of surgical resection, radiation and chemotherapy produces a median survival of only 12-15 months. Therefore, there is a need to develop new therapeutic approaches for the treatment of GBM. This thesis investigates a new series of synthetic cancer vaccines, conjugating tumour-associated antigens (TAAs) to an isomer of ɑ-Galactosylceramide (ɑ-GalCer), a potent invariant natural killer T (iNKT) cell agonist with documented adjuvant activity. Upon antigen encounter, activated iNKT cells are capable of licensing dendritic cells (DCs) through CD40:CD40L interactions and cytokine production. The licensed DCs subsequently stimulate potent CD8⁺ T cell responses, capable of killing cancerous tissue. Conjugation of ɑ-GalCer to the TAA-derived peptide was achieved via an enzymatically cleavable linker sensitive to cathepsin B activity. This strategy allows co-delivery of the active components, with the rationale that the same DC will be able to co-present both ɑ-GalCer for iNKT cell activation, and peptide to induce an enhanced CD8⁺ T cell responses. The conjugate vaccines assessed in this thesis were able to induce iNKT cell activation and produce CD8⁺ T cell cytoxicity. However, this did not correlate with in vivo antitumour activity, as the vaccine that incorporated the TAA survivin, produced minimal cytotoxicity but potent anti-tumour responses against an implantable model of glioma. Enhancing T cell-mediated immune responses has been validated by immune checkpoint inhibition for the treatment of cancer. However, many patients do not respond to the therapy. It is thought that this subset of patients may lack pre-existing T cell responses, which are required for the efficacy of checkpoint inhibition. Therefore, there is considerable interest in whether the use of vaccines that stimulate T cell activation can improve responses to checkpoint blockade and other immune modulating drugs. The survivin vaccine was combined with the immune checkpoint blockade inhibitors ɑ-PD-1, ɑ-CTLA-4 and ɑ-LAG-3, the co-stimulatory agent a-4-1BB, or administered with T regulatory cell (TREG) depletion, to reveal the immunogenicity of the vaccine. This research revealed that combining the survivin vaccine with the immune checkpoint inhibitor ɑ-CTLA-4 improved overall survival of mice, compared to the vaccine alone. This finding suggests that this combined therapy may be a useful immunotherapeutic strategy for the treatment of GBM.</p>
Coinhibitory Receptor Expression and Immune Checkpoint Blockade: Maintaining a Balance in CD8+ T Cell Responses to Chronic Viral Infections and Cancer
