CELLULAR CANCER VACCINES

描述(申请人提供)：这笔赠款的目标是更好地了解共刺激作用的基本免疫生物学，并设计独特的癌症免疫治疗策略，以新的方式调用共刺激作用。本申请中所倡导的策略是我们的研究团队十年来努力创新的蛋白质转移方法的产物，这些方法可用于共刺激分子“绘制”，作为实现定量和组合共刺激分子neo表达的授权手段。因此，蛋白质转移从一开始就代表了这一系列研究的驱动概念和特点，也是它有别于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地方。在目前的赠款过程中，蛋白质转移工具和转移的蛋白质都得到了发展，值得注意的是，在上一个资助期中途出现了两种蛋白质转移方式：1)一种简单的双组分蛋白质转移方法，它使用棕榈酸蛋白A：共刺激分子FcGamma1结合作为“共刺激分子涂料”，并使肿瘤内、多个共刺激分子接种成为可能；以及2)一种新的可溶的“反式信号转换蛋白(TSCP)”，本质上构成了“可注射涂料”。这一新的应用提供了两个特定的目标，利用这两种新的蛋白质转移方式中的第一种：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细胞激活阈值的定量和协同效应，并建立在用于主动癌症免疫治疗的这种共刺激模式的基础上--通过瘤内的组合棕榈化蛋白A：共刺激分子。FcGamma1蛋白转移方法我们创新；2)探索我们发现的顺式自共刺激现象的免疫生物学方面，重点是共刺激分子绘制的T细胞激活状态的功能和分子特征，并将这种共刺激模式建立在被动癌症免疫治疗的基础上-通过过继转移的共刺激分子绘制的T细胞来增强抗肿瘤免疫。

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.