Vaccine and Immunomodulatory Strategies to Target the Cancer Mutanome

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Skills Priority Alignment: Quantitative BiologyCancer immunotherapy covers a wide range of approaches that seek to equip the immune system to identify and eliminate tumour cells. Used in isolation, these approaches show promising results in improving tumour clearance and survival, however they are often limited by the ability of tumour cells to rapidly evolve mechanisms that aid immune evasion and tumour progression. We seek to focus on amplifying the differences between healthy and malignant cells, and explore the use of combination immunotherapy to target multiple pathways and achieve effective anti-tumour immunity. Cancers are characterised by uncontrolled cell growth that is primarily driven by acquired somatic mutations in the genome. Next generation sequencing (NGS) approaches have helped mutations in protein-coding, exonic regions that generate neoantigens that are not encoded by the germline genome. These tumour specific antigens are ideal targets for immunotherapy as they have not been subject to immune intolerance mechanisms. The increased protection and survival seen in preclinical melanoma models receiving neoantigen-specific RNA and peptide vaccines has been translated in the clinic. However, this vaccine-based approach required subsequent treatment with PD-1 blockade, indicating that vaccine-based combination immunotherapy with immune checkpoint inhibitors can potentially help establish lasting anti-tumour immunity. Therefore, this project seeks to develop vaccine-based immunotherapeutic strategies to target the mutanome in both a solid tumour (Head and Neck Squamous Cell Carcinoma (HNSCC)) and a lethal haematological malignancy (Multiple Myeloma (MM)).