CELLULAR CANCER VACCINES

描述（由申请人提供）：该基金的目的是更好地了解共刺激的基本免疫生物学，并设计独特的癌症免疫策略，以新的方式调用共刺激。本申请中倡导的策略是我们的研究团队长达十年的努力的结果，以创新可用于共刺激分子“绘画”的蛋白质转移方法，作为实现定量和组合共刺激分子新表达的授权手段。因此，蛋白质转移从一开始就代表了这一研究领域的驱动概念和显著特征，这是它与其他地方应用于癌症免疫治疗的更广泛的基于基因治疗的策略的区别。在当前的资助过程中，蛋白质转移工具和转移的蛋白质都发生了变化，并且值得注意的是，在最后一个资助期的中途出现了两种蛋白质转移模式：1）简单的双组分蛋白质转移方法，其使用棕榈酸化蛋白A：共刺激因子Fc γ 1缀合物作为“共刺激因子涂料”，并且能够进行肿瘤内、多共刺激因子疫苗接种;和2）一类新的可溶性“反式信号转换蛋白（TSCP）”，其实质上构成“可注射涂料”。“这项更新申请提供了两个具体的目标，利用这两种新的蛋白质转移模式中的第一种：1）分析跨细胞间共刺激的免疫生物学方面，重点是共刺激对T细胞活化阈值的定量和协同作用，并基于这种共刺激模式用于主动癌症免疫治疗-细胞癌症疫苗接种，通过肿瘤内，我们创新的组合棕榈酸蛋白A：共刺激因子Fc γ 1蛋白转移方法;和2）探索我们发现的顺式自身共刺激现象的免疫生物学方面，重点关注共刺激物涂染的T细胞的活化状态的功能和分子特征，并在此基础上建立被动癌症免疫疗法的共刺激模式-通过使用过继转移的共刺激物涂染的T细胞赋予抗肿瘤免疫力。

DESCRIPTION (provided by applicant): The objectives of this grant are to better understand the basic immunobiology of costimulation and to design unique cancer immunotherapeutic strategies that invoke costimulation in new ways. The strategies advocated in this application are outgrowths of a decade-long effort by our investigative team to innovate protein transfer methods that can be used for costimulator "painting," as an empowering means for achieving quantitative and combinatorial costimulator neo-expression. Thus, protein transfer represents the driving concept and distinguishing feature of this line of investigation from its inception, and it is what sets it apart from the more widespread gene therapy-based strategies that are being applied elsewhere to cancer immunotherapy. Over the course of the current grant, both the protein transfer tools and the proteins transferred have evolved, and significantly, two protein transfer modalities emerged midway through the last funding period: 1) a simple two-component protein transfer method that uses palmitated-protein A:costimulator Fcgamma1 conjugates as "costimulator paints," and enables intratumoral, multi-costimulator vaccination; and 2) a new class of soluble "trans signal converter proteins (TSCP)," which in essence constitute "injectable paints." This renewal application offers two specific aims that leverage the first of these two new protein transfer modalities: 1) Analyzing immunobiological aspects of trans intercellular costimulation, with a focus on quantitative and synergistic effects of costimulation on T cell activation thresholds, and building upon this mode of costimulation for active cancer immunotherapy -- cellular cancer vaccination, via the intratumoral, combinatorial palmitated protein A:costimulator.Fcgamma1 protein transfer method that we innovated; and 2) Exploring immunobiological aspects of the cis auto-costimulation phenomenon that we discovered, with a focus on functional and molecular features of the activation state of costimulator-painted T cells, and building upon this mode of costimulation for passive cancer immunotherapy -- conferring anti-tumor immunity via the use of adoptively-transferred, costimulator-painted T cells.