Chemical Remodeling of Cell Surface to Enhance the Accumulation of Therapeutic Bacteria to Tumors

项目总结 我们的研究团队正在提议建立一种替代类型的癌症免疫疗法，其核心是 肿瘤内选择性和局限性的细菌感染。可行的假设是，导演 细菌选择性地作用于肿瘤块将通过患者自身的免疫促进肿瘤的清除 系统。因为使用的细菌不会有抗药性(我们可以决定植入哪些细菌)， 细菌感染可以在需要时通过应用抗生素而很容易清除。我们建议控制 通过将肿瘤定位表位移植到细菌细胞表面来定位和黏附细菌。一次 它们到达肿瘤，少量的细菌就会生长、繁殖，并嵌入到肿瘤中。 目的1.我们将建立一个筛选平台，以有效地鉴定表面可以坚固的细菌 经过化学改造。表面重塑将基于类似物的新陈代谢合并进行 表面结合生物大分子的前体。这些生物大分子的保守性，他们的 暴露于细胞外空间，并建立了用非自然表位标记代谢的方法 为化学接枝肿瘤结合剂提供了基础。 目的2.我们将肿瘤靶向部分移植到从目标1中选择的细菌的表面，以完善集合 根据它们与癌细胞特异性结合的能力对候选细菌进行分类。我们将使用两种方式 肿瘤靶向：肿瘤生物标记物在癌细胞表面过表达，并且 肿瘤固有的低pH微环境。 目的3.我们将评估表面重编程细菌(在目标2中选择)的肿瘤靶向和定植 在小鼠的异种移植癌模型中。将对各种组织和血液中的细菌负荷水平进行量化，以 确定细菌的定植情况。

PROJECT SUMMARY Our research team is proposing to establish an alternative type of cancer immunotherapy centered on a selective and localized bacterial infection within the tumor mass. The working hypothesis is that directing bacteria selectively to a tumor mass will promote the clearance of the tumor by the patient’s own immune system. Because the bacteria used will not be drug resistant (we can dictate which bacteria are implanted), the bacterial infection can be readily cleared when needed by the application of antibiotics. We propose to control the localization and adhesion of bacteria by grafting tumor-homing epitopes onto bacterial cell surfaces. Once they reach the tumor, the small number of bacteria will grow, multiply, and imbed into the tumor. Aim 1. We will set up a screening platform to efficiently identify bacteria whose surface can be robustly chemically remodeled. Surface remodeling will be performed based on the metabolic incorporation of analogs of precursors to surface bound biomacromolecules. The conserved nature of these biomacromolecules, their exposure to the extracellular space, and established methods of metabolic labeling with unnatural epitopes provides the basis to chemically graft tumor-binding agents. Aim 2. We will graft tumor-targeting moieties onto the surface of bacteria selected from Aim 1 to refine the set of candidate bacteria based on their ability to specifically bind to cancer cells. We will use two modalities of tumor-targeting: cancer biomarkers overexpressed overexpressed on the surface of cancer cells, and the inherently low pH microenvironment of tumors. Aim 3. We will evaluate tumor targeting and colonization by surface reprogrammed bacteria (selected in Aim 2) in xenograft cancer models in mice. Bacterial load levels will be quantified in various tissues and in blood to determine the colonization of bacteria.