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，它可以潜在地取代高度侵入性的手术，放疗和化疗方法。然而，由于肿瘤相关碳水化合物和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。开发新的疫苗策略和抗原递送的新方法来训练免疫系统有效地识别肿瘤抗原并发起有效的免疫反应是至关重要的。在本研究中，病毒样颗粒（vlp）将作为一种新的抗原递送平台，引发强大的抗癌免疫反应。中心假设是肿瘤相关碳水化合物抗原（TACAs）在自组装VLP表面的高度有组织的展示将大大增强对TACAs的体液反应。目的1：开发豇豆花叶病毒（CPMV） VLP作为载体，增强对TACAs的免疫应答。利用CPMV作为载体，获得了高滴度的针对TACAs的特异性抗体，取得了可喜的初步结果。在小鼠肿瘤模型中，产生的抗体不仅能识别癌细胞上显示的抗原，还能延缓肿瘤的生长。将系统地改变CPMV结构，以确定连接体类型、表位密度、显示模式和佐剂对免疫反应的影响。在目标2中，将研究另一种有前途的VLP噬菌体Qb作为TACAs的载体。多个vlp的可用性将使异种启动-增强策略的发展成为可能，其中体液反应将被引导集中在TACA表位上，减少抗载流子反应。在目标3中，TACA、T细胞表位和佐剂将被整合到一个VLP结构中。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。这种多组分结构将在使用小鼠肿瘤模型的免疫治疗和免疫保护设置中进行评估。产生的综合免疫反应可能对根除肿瘤更有效。所提出的研究不仅将大大提高对抗原密度、抗原模式和连接物对免疫反应的影响的基本认识，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. PUBLIC HEALTH RELEVANCE: Cancer is a major cause of mortality in the world. In this project, novel vaccine delivery systems will be developed to induce strong and comprehensive immune responses against tumor, which can greatly enhance our knowledge on effective anti-cancer vaccine constructs.