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

细胞表面的化学重塑以增强治疗性细菌对肿瘤的积累

• 批准号: 10535464
• 负责人: Marcos M. Pires
• 金额: $ 21.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535464
• 关键词: Adhesions; Antibiotics; Antineoplastic Agents; Attenuated; Bacteria; Bacterial Adhesins; Bacterial Infections; Binding; Blood; Breast Cancer Model; Cancer Model; Cancer Patient; Cancer cell line; Cell surface; Cementation; Chemicals; Chemotherapy and/or radiation; Complement; Development; Dose; Drug resistance; Engineering; Epitopes; Exhibits; Exposure to; Extracellular Space; Face; Folic Acid; Genetically Modified Organisms; Genus Mycobacterium; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Homing; Immune Targeting; Immune response; Immune system; Immunologics; Immunology; Immunotherapy; Implant; Infection; Label; Laboratories; Libraries; Lipopolysaccharides; Malignant Neoplasms; Measurable; Measures; Metabolic; Methods; Microbiology; Modality; Modernization; Modification; Mus; Nature; Pathogenicity; Patients; Peptides; Peptidoglycan; Proteins; Radiation therapy; Research; Safety; Seminal; Site; Solid Neoplasm; Streptococcus; Supplementation; Surface; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxin; Treatment Efficacy; United States National Institutes of Health; Variant; Virulence; Work; Xenograft procedure; analog; anti-cancer; arm; base; biomacromolecule; cancer biomarkers; cancer cell; cancer immunotherapeutics; cancer immunotherapy; cancer therapy; cancer type; candidate selection; chemotherapeutic agent; clinical translation; combat; fluorophore; folate-binding protein; genetic manipulation; immunogenicity; improved; infection risk; innovation; microbial; neoplastic cell; novel; overexpression; patient response; preclinical development; screening; tumor; tumor immunology; tumor microenvironment

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.

项目摘要 我们的研究小组正在建议建立一种替代类型的癌症免疫疗法， 肿瘤块内的选择性和局部细菌感染。工作假设是， 细菌选择性地进入肿瘤块将促进患者自身免疫系统清除肿瘤 系统因为使用的细菌不会产生抗药性（我们可以决定植入哪些细菌）， 细菌感染在需要时可通过应用抗生素而容易地清除。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定位和粘附细菌。一旦 当它们到达肿瘤时，少量的细菌会生长、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牢固粘附的细菌。 化学重塑将基于类似物的代谢结合进行表面重塑 表面结合生物大分子的前体。这些生物大分子的保守性， 暴露于细胞外空间，并建立了用非天然表位进行代谢标记的方法 为化学移植肿瘤结合剂提供了基础。 目标2.我们将肿瘤靶向部分移植到从Aim 1中选择的细菌的表面上，以完善该集合。 候选细菌基于它们特异性结合癌细胞的能力。我们将使用两种方法 肿瘤靶向：在癌细胞表面过表达的癌症生物标志物， 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（在目标2中选择）的肿瘤靶向和定植 在小鼠异种移植癌症模型中。将对各种组织和血液中的细菌负荷水平进行定量， 确定细菌的定植。