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

描述（由申请人提供）：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，它可以潜在地替代高度侵入性的手术，放射和化疗方法。然而，由于肿瘤相关的碳水化合物和肽抗原的低免疫原性，开发针对癌症的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产生有效的免疫应答。在这项提议中，病毒样颗粒（VLP）将被视为一种新的抗原递送平台，以引发强大的抗癌免疫反应。中心假设是自组装VLP表面上的肿瘤相关碳水化合物抗原（TACA）的高度组织化展示将极大地增强对TACA的体液应答。在目标1中，将开发豇豆花叶病毒（CPMV）VLP作为载体来增强对TACA的免疫应答。已经获得了有希望的初步结果，其中使用CPMV作为载体引起针对TACA的高滴度的特异性抗体。产生的抗体不仅识别癌细胞上展示的抗原，而且还延迟了小鼠肿瘤模型中的肿瘤生长。将系统地改变CPMV构建体以确定接头类型、表位密度、展示模式和佐剂对免疫应答的影响。目的二是研究另一种有前途的VLP噬菌体Qb作为TACA的载体。多个VLP的可用性将使得能够开发异源初免-加强策略，其中体液应答将被引导以集中于具有降低的抗载体应答的TACA表位。在目标3中，TACA、T细胞表位和佐剂将被掺入到一个VLP构建体上。这不仅可以参与免疫系统的体液手臂，还可以同时激活细胞免疫。将使用小鼠肿瘤模型在免疫治疗和免疫保护环境中评价该多组分构建体。产生的全面免疫反应可能对根除肿瘤更有效。所提出的研究不仅将极大地增强对抗原密度、抗原模式化和接头对免疫应答的影响的基本理解，而且还将为抗癌疫苗的未来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.