Optimization of Tumor Vaccines for the Aged

描述（由申请人提供）：与年龄相关的癌症增加可能部分是由于免疫功能的整体下降。人们一直认为，这种免疫功能的丧失是衰老的淋巴样细胞固有的（即衰老的T细胞有缺陷）。然而，我们实验室利用肿瘤模型的最新数据表明，如果免疫反应在共刺激分子的存在下被刺激，幼稚的老年CDS1 T细胞能够以与年轻CD8+ T细胞相同的活力经历初级激活，包括长期记忆反应的发展。这些结果表明，老年小鼠确实拥有功能性T细胞库，如果有足够的共刺激，这些T细胞库可以被激活和扩增。这些数据使我们提出了一个假设，即老化的T细胞库可以用于诱导肿瘤免疫。然而，为了有效地刺激抗肿瘤反应，确定和优化疫苗接种方案是至关重要的，这将导致产生初级和持久的记忆反应。本提案将评估疫苗接种策略，其中每个系统使用不同的作用模式来靶向和激活抗原提呈细胞（APCs）以增加抗原提呈。我们将利用三种不同的“佐剂/疫苗”，如腺病毒、鞭毛蛋白融合蛋白或补体衍生融合蛋白，与共刺激分子（如抗ox40或抗4- lbb）结合，优化老年宿主的抗肿瘤免疫反应。为了研究这些疫苗的功效并优化它们，我们将使用两种不同的肿瘤模型：第一种模型使用增强型绿色荧光蛋白（EGFP）作为替代肿瘤抗原来评估对非自身抗原的强效抗原的免疫反应。第二种模型利用Her-2/neu蛋白，这是一种与临床更相关的肿瘤抗原，它是一种自身抗原。在目的1中，我们将比较接种腺病毒、鞭毛蛋白融合蛋白或表达EGFP或Her-2/neu基因/蛋白的补体衍生融合蛋白后，年轻和年老小鼠体外CDS T细胞的反应。我们将比较不同的剂量和途径，并随着时间的推移跟踪原发和记忆反应的持久性和有效性。这些实验将使我们能够确定哪种方案在老年小鼠中诱导最强和持久的免疫反应。目标2将测试最有效的疫苗接种方案（在目标1中定义），以诱导保护性免疫或治疗已确定的肿瘤。根据我们在动物肿瘤模型中积累的数据，我们预测免疫治疗可以显著延缓肿瘤的生长，但不足以完全消除老年人的肿瘤。在Aim 3中，我们将验证靶向免疫治疗与抗血管生成治疗联合可以协同作用的假设，为老年动物完全消除肿瘤提供更有效的机制。从这些研究中获得的信息可能对老年人疫苗接种策略的发展具有重要的临床意义。

DESCRIPTION (provided by applicant): The age-associated increase in cancer may be due in part to a global decrease in immune function. It has been thought that this loss of immune function was intrinsic to the aged lymphoid cells (i.e. aged T cells are defective). However, recent data from our laboratory utilizing a tumor model indicate that if the immune response is stimulated in the presence of co-stimulatory molecules, naive aged CDS1 T cells are able to undergo primary activation with the same degree of vigor as that of young CD8+ T cells, including the development of long-lasting memory responses. These results show that old mice do possess a functional T cell repertoire that can be activated and expanded if there is sufficient costimulation. This data led us to propose the hypothesis that the aged T cell repertoire can be exploited for the induction of tumor immunity. However, to effectively stimulate an antitumor response it is critical to identify and optimize vaccination protocol(s) that will result in the generation of primary and long-lasting memory responses. This proposal will evaluate vaccination strategies in which each system uses a different mode of action to target and activate antigen-presenting cells (APCs) to increase antigen presentation. We will utilize three different "adjuvants/vaccines" such as Adenoviruses, flagellin-fusion proteins or complement-derived-fusion proteins in combination with costimulatory molecules such as anti-OX40 or anti-4-lBB to optimize antitumor immune responses in old hosts. To investigate the efficacy and optimize these vaccines, we will use two different tumor models: The first model utilizes the Enhanced Green Fluorescent protein (EGFP) as a surrogate tumor antigen to evaluate immune responses to a potent antigen in which it is not a self-antigen. The second model utilizes the Her-2/neu protein that is a more clinical relevant tumor antigen in which it is a self-antigen. In aim 1 we will compare in vitro CDS T cell responses of young and old mice after vaccination with the Adenoviruses, flagellin-fusion proteins or complement-derived-fusion proteins expressing the EGFP or Her-2/neu gene/protein. We will compare different doses and routes and follow the persistence and effectiveness of the primary and memory responses over time. These experiments will allow us to define which protocol induces the strongest and persistent immune response in old mice. Aim 2 will test the most efficient vaccination protocol (defined in Aim 1) to induce protective immunity or for the treatment of established tumors. Based on the accumulative data we have generated with our animal tumor models, we predict that immunotherapy treatment could substantially delay the tumor growth but it will not be sufficient for the complete elimination of tumors in the aged. In Aim 3 we will test the hypothesis that targeted immunotherapy in combination with antiangiogenic therapy can be synergistic rendering a more efficient mechanism for the complete elimination of tumor in old animals. The information gained from these studies could have important clinical implications for the development of vaccination strategies in the elderly.