The Development of Cancer Vaccines Targeting Neoantigens for the Treatment of Malignant Astrocytomas
Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Conventional therapies for GBM typically fail to provide lasting antitumor benefits, owing to their inability to specifically eliminate all malignant cells. Immunotherapy is currently being pursued as a strategy to address this unmet need, in light of the cell-specific cytotoxicity an immune response can afford. Of the various immunotherapeutic modalities, cancer vaccines are currently being evaluated as a means to direct the adaptive immune system to target residual GBM cells that remain following standard-of-care treatment. To date, no cancer vaccines have been proven effective against GBM; however, only a few have reached phase III clinical testing. Clinical immunological monitoring data suggests that GBM vaccines are capable of stimulating immune responses reactive to GBM antigens, but whether these responses have an appreciable antitumor effect on GBM is still uncertain. Nevertheless, there have been several promising outcomes in early phase clinical trials, which lend encouragement to this area of study.
In this dissertation, we explore the therapeutic potential of cancer vaccines targeting malignant astrocytoma-specific somatic missense mutations – or neoantigens. This pursuit was inspired by recent data from a phase III clinical trial with a protein vaccine targeting the GBM-specific antigen EGFRvIII, revealing that most recurrent tumors were composed of EGFRvIII-deficient or -suppressed tumor cell variants. This outcome, known as antigen escape, is likely a consequence of the profound heterogeneity of GBM tumors and, altogether, suggests that monovalent immunotherapeutic strategies targeting subclonal GBM antigens are likely insufficient to treat this disease. Conversely, personalized cancer vaccines targeting patient-specific missense mutations have the potential to elicit a multivalent, tumor-specific immune response that may target a broader repertoire of GBM cells.
Chapters 1-4 offer a comprehensive review of GBM, an overview of immunotherapy for malignant brain tumors, and promising vaccines that are currently being explored for the treatment of GBM. In chapter 5, we present a novel method that we have developed for evaluating neoantigen-specific lymphocytes from miniscule amounts of solid tumor tissue, which we believe can aid in immunological monitoring of neoantigen-specific immune responses in the clinic. In chapter 6, we elucidate the mechanism of an efficacious neoantigen vaccine, which led to the development of rationally-designed, neoantigen-targeting, synthetic long peptide vaccines with enhanced immunogenicity and efficacy using a universal helper epitope. In chapter 7, we explore the utility of minigene-transfected dendritic cell (DC) vaccines for targeting neoantigens, in which we reveal several significant limitations of traditional GM-CSF + IL-4-generated DCs. Finally, chapter 8 discusses future prospects for enhancing the therapeutic response by cancer vaccines. Together, this original work provides several encouraging insights for the development and evaluation of personalized cancer vaccines for GBM.
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