Vaccine and Immunomodulatory Strategies to Target the Cancer Mutanome

技能优先调整：定量生物学癌症免疫疗法涵盖了一系列寻求装备免疫系统以识别和消除肿瘤细胞的方法。单独使用时，这些方法在改善肿瘤清除和存活率方面显示出有希望的结果，但它们往往受到肿瘤细胞快速进化机制以帮助免疫逃避和肿瘤进展的能力的限制。我们寻求将重点放在放大健康和恶性细胞之间的差异，并探索使用联合免疫疗法来靶向多个途径，实现有效的抗肿瘤免疫。癌症的特征是细胞生长不受控制，这主要是由基因组中获得的体细胞突变推动的。下一代测序(NGS)方法已经帮助蛋白质编码的外显子区域发生突变，这些外显子区域产生了不是由生殖系基因组编码的新抗原。这些肿瘤特异性抗原是免疫治疗的理想靶点，因为它们尚未受到免疫耐受机制的影响。在接受新抗原特异性RNA和多肽疫苗的临床前黑色素瘤模型中看到的增加的保护和存活率已经在临床上得到了转化。然而，这种基于疫苗的方法需要随后使用PD-1阻断治疗，这表明基于疫苗的免疫疗法与免疫检查点抑制剂相结合可能有助于建立持久的抗肿瘤免疫。因此，该项目寻求开发基于疫苗的免疫治疗策略，以针对实体肿瘤(头颈部鳞状细胞癌(HNSCC))和致命性血液系统恶性肿瘤(多发性骨髓瘤(MM))的突变组。

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)).