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

基本信息

批准号：
10391986
负责人：
Marcos M. Pires
金额：
$ 19.75万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391986
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 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 Immuno-Chemotherapy Immunologics Immunology 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 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

Adhesions Antibiotics Antineoplastic Agents Attenuated Bacteria Bacterial Adhesins Bacterial Infections Binding Blood Breast Cancer Model Cancer Model Cancer Patient Cancer cell line Cell surface 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 Immuno-Chemotherapy Immunologics Immunology 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 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

展开

项目摘要

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团队提议建立一种替代类型的癌症免疫疗法肿瘤质量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对肿瘤质量有选择性地促进患者自身免疫的清除肿瘤系统。因为所使用的细菌不会是耐药性的（我们可以决定植入哪种细菌），所以通过应用抗生素，可以在需要时很容易清除细菌感染。我们建议控制通过将肿瘤的表位接纳到细菌细胞表面上的细菌的定位和粘合剂。一次它们到达肿瘤，少量细菌会生长，繁殖并嵌入到肿瘤中。目标1。我们将建立一个筛选平台，以有效识别其表面可靠的细菌化学重塑。表面重塑将根据类似物的代谢结合进行表面结合的生物大分子的前体。这些生物大分子的保守性质，它们暴露于细胞外空间，并用不自然表位的代谢标记的建立方法为化学移植物肿瘤结合剂提供了基础。 AIM 2。我们将把靶向肿瘤的部分移植到AIM 1中选择的细菌表面以完善集合候选细菌的特异性与癌细胞结合的能力。我们将使用两种方式靶向肿瘤：癌症生物标志物在癌细胞表面过表达，并固有的低pH肿瘤微环境。 AIM 3。我们将通过表面重编程的细菌评估肿瘤靶向和定植（在AIM 2中选择）在小鼠的Xenographic Cancer模型中。细菌负荷水平将在各种时间和血液中进行量化确定细菌的定殖。