Virus-Like Particle Based Antigen Display as Multi-component Anticancer Vaccines

描述(申请人提供)：利用人体免疫系统的力量来预防和治疗癌症是一种非常有吸引力的方法，它有可能取代高侵入性的手术、放射和化疗方法。然而，由于肿瘤相关碳水化合物和多肽抗原的免疫原性较低，开发抗癌疫苗是一项极具挑战性的任务。至关重要的是，可以开发新的疫苗策略和新的抗原递送方法，以训练免疫系统有效地识别肿瘤抗原并建立有效的免疫反应。在这项提案中，病毒样颗粒(VLP)将被视为一种新的抗原传递平台，以诱导强大的抗癌免疫反应。中心假设是在自组装的VLP表面高度有序地展示肿瘤相关碳水化合物抗原(TACAs)将大大增强对TACAs的体液反应。在目标1中，将开发豌豆花叶病毒(CPMV)VLP作为载体来增强对TACAs的免疫应答。在以CPMV为载体的TACAs诱导出高滴度的特异性抗体方面，取得了有希望的初步结果。产生的抗体不仅识别癌细胞上显示的抗原，还在小鼠肿瘤模型中延缓了肿瘤的生长。CPMV结构将被系统地改变，以确定连接子类型、表位密度、展示模式和佐剂对免疫反应的影响。在目标2中，将研究另一种很有前途的VLP噬菌体QB作为TACA的载体。多个VLP的可获得性将使异源Prime-Boost策略的发展成为可能，其中体液反应将被定向到TACA表位上，并减少抗载体反应。在目标3中，TACA、T细胞表位和一个佐剂将被整合到一个VLP构建体上。这不仅可以激活免疫系统的体液臂，还可以同时激活细胞免疫。这种多组分的构建将在免疫治疗和免疫保护环境中使用小鼠肿瘤模型进行评估。产生的全面免疫反应可能会更有效地根除肿瘤。这些研究不仅将极大地加强对抗原密度、抗原构型和连接物对免疫应答影响的基本了解，而且还将为未来抗癌疫苗的临床评价提供有价值的临床前信息。

DESCRIPTION (provided by applicant): Harnessing the power of body's immune system to prevent and treat cancers is a highly attractive approach, which can potentially substitute the highly invasive surgery, radiation and chemotherapy methods. However, the development of vaccines against cancer is an immensely challenging task due to the low immunogenicity of tumor associated carbohydrate and peptide antigens. It is crucial that new vaccine strategies and new methods of antigen delivery can be developed to train the immune system to efficiently recognize tumor antigens and mount an effective immune response. In this proposal, virus like particles (VLPs) will be examined as a new antigen delivery platform to elicit powerful anti-cancer immune responses. The central hypothesis is that highly organized display of tumor associated carbohydrate antigens (TACAs) on the self-assembled VLP surface will greatly enhance the humoral responses to the TACAs. In aim 1, Cowpea Mosaic Virus (CPMV) VLP will be developed as a carrier to boost the immune responses to TACAs. Promising preliminary results have been obtained where high titers of specific antibodies were elicited against TACAs using CPMV as the carrier. The antibodies generated not only recognized the antigen displayed on cancer cells but also delayed tumor growth in a mouse tumor model. The CPMV constructs will be systematically varied to determine the effects of linker type, epitope density, display patterns and adjuvants on immune responses. In aim 2, another promising VLP bacteriophage Qb will be studied as the carrier for TACAs. The availability of multiple VLPs will enable the development of a heterologous prime-boost strategy, where the humoral responses will be directed to focus on the TACA epitopes with reduced anti-carrier responses. In aim 3, TACA, T cell epitopes and an adjuvant will be incorporated onto one VLP construct. This can not only engage the humoral arm of the immune systems, but also activate the cellular immunity simultaneously. This multi-component construct will be evaluated in both immuno-therapeutic and immune-protective settings using mouse tumor models. The comprehensive immune response generated can potentially be much more potent towards eradicating the tumor. The proposed studies will not only greatly enhance the basic understanding of the effects of antigen density, antigen patterning, and linkers on immune responses but also provide valuable pre- clinical information for future clinical evaluation of anti-cancer vaccines.