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

项目概要 我们的研究团队提议建立一种以癌症免疫疗法为中心的替代类型 肿瘤块内的选择性和局部细菌感染。工作假设是指导 细菌选择性地作用于肿瘤块，会促进患者自身免疫对肿瘤的清除 系统。因为所使用的细菌不会产生耐药性（我们可以决定植入哪些细菌）， 需要时使用抗生素可以轻松清除细菌感染。我们建议控制 通过将肿瘤归巢表位移植到细菌细胞表面来实现细菌的定位和粘附。曾经 当它们到达肿瘤时，少量细菌就会生长、繁殖并嵌入肿瘤中。 目标1.我们将建立一个筛选平台，以有效地识别表面可以鲁棒的细菌 经过化学改造。表面重塑将基于类似物的代谢掺入进行 表面结合生物大分子的前体。这些生物大分子的保守性，它们的 暴露于细胞外空间，并建立了非自然表位代谢标记的方法 为化学移植肿瘤结合剂提供了基础。 目标 2. 我们将把肿瘤靶向部分移植到从目标 1 中选择的细菌表面以完善该组 根据候选细菌与癌细胞特异性结合的能力来筛选候选细菌。我们将使用两种方式 肿瘤靶向：癌症生物标志物在癌细胞表面过度表达，并且 肿瘤固有的低pH微环境。 目标 3. 我们将评估表面重编程细菌的肿瘤靶向和定植（在目标 2 中选择） 在小鼠异种移植癌症模型中。将量化各种组织和血液中的细菌负荷水平，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.