Optimization of CAR-Bacteria for Oral Cancer

口腔癌 CAR 细菌的优化

基本信息

批准号：
10648292
负责人：
Jack D Bui
金额：
$ 22.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648292
关键词：
Affinity Animal Model Antigen Targeting Bacteria Bilateral Binding Cell Death Cell Line Cells Cervical Complex Cytolysis Data Dose Engineering Engraftment Evolution Future Goals Growth HLA-A2 Antigen Head and Neck Cancer Human Human Cell Line Human Papillomavirus Innate Immune Response Kinetics Label Libraries Major Histocompatibility Complex Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Mediating Methods Molecular Evolution Mouthwash Mus Oncoproteins Pattern Peptide/MHC Complex Peptides Pharmaceutical Preparations Physiologic pulse Population Density Production Proteins Research Specificity T-Lymphocyte Therapeutic Toxic effect Treatment Efficacy Tumor Specific Peptide Viral Work Xenograft Model antigen challenge cancer cell chimeric antigen receptor experimental study human model improved in vivo innovation intraperitoneal invention knock-down malignant mouth neoplasm nanobodies neoplastic cell novel oral bacteria overexpression prevent response systemic toxicity technology platform tumor tumor growth tumor immunology

项目摘要

ABSTRACT The goal of this project is to explore the feasibility of generating Chimeric Antigen Receptors (CARs) expressed by bacteria. Instead of using T cells, we propose to explore the idea and use of bacteria to mediate the targeted destruction of cancer cells. In addition, we explore the possibility that we could target CAR-bacteria to specific major histocompatibility complex (MHC)-neopeptide complexes (pMHC) on tumor cells. We call these engineered bacteria cells CAR-bacteria. Current CAR-expressing T cells provide durable responses but have three main limitations: specificity, toxicity, and feasibility. This study will address all three concerns. In this proposal, we target engineered bacterial lysis to head and neck or cervical cancer cells expressing HLA-A2-E7, a known pMHC on tumor cells infected by human papilloma virus (HPV). The targeting enables anti-tumor protein production only when a predefined population density of bacteria is reached. This method should dramatically reduce bacterial colony size and greatly lowers/prevents systemic toxicities. The approach has the potential to be a therapeutic in HPV-positive oral cancer as it could be administered and controlled as a bacterial mouthwash. This project combines two innovations leveraging a Synthetically-Evolved Nanobody (SEN) library proven capable of selectively binding MHC-peptide complexes and combining this specific cancer cell targeting with synchronized circuit lysis to create CAR-bacteria. Our proposed studies provide proof-of-concept that (1) CARs can be produced that recognize pMHC, (2) CAR-bacteria localization and colonization can be controlled by tumor expression of certain pMHC and (3) CAR-bacteria have therapeutic activity against tumor cells that express specific pMHC. We accomplish these proof-of-concept studies via the following two objectives: (1) Optimize binding and specificity of CAR-bacteria to HLA-A2-E7 and (2) Check efficacy of CAR-bacteria in an animal model of head and neck and cervical cancer.

抽象的该项目的目标是探索生成嵌合抗原受体（CAR）的可行性由细菌表达。我们建议不使用 T 细胞，而是探索细菌介导的想法和用途有针对性地破坏癌细胞。此外，我们还探索了针对 CAR 细菌的可能性肿瘤细胞上特定的主要组织相容性复合物（MHC）-新肽复合物（pMHC）。我们称这些为工程细菌细胞CAR-细菌。目前表达 CAR 的 T 细胞可提供持久的反应，但三个主要局限性：特异性、毒性和可行性。这项研究将解决所有三个问题。在这个建议，我们针对表达 HLA-A2-E7 的头颈或宫颈癌细胞进行工程细菌裂解，已知的 pMHC 与人乳头瘤病毒 (HPV) 感染的肿瘤细胞有关。靶向使抗肿瘤蛋白成为可能仅当达到预定的细菌种群密度时才进行生产。该方法应该显着减少细菌菌落大小并大大降低/防止全身毒性。该方法有潜力可以作为 HPV 阳性口腔癌的治疗剂，因为它可以作为细菌漱口水进行施用和控制。该项目结合了两项创新，利用经过验证的合成进化纳米抗体 (SEN) 库能够选择性地结合 MHC-肽复合物，并将这种特定的癌细胞靶向与同步电路裂解以产生 CAR 细菌。我们提出的研究提供了以下概念验证：(1) CAR 可以生产识别pMHC，（2）CAR-细菌定位和定植可以由肿瘤控制 (3) CAR-细菌对表达某些 pMHC 的肿瘤细胞具有治疗活性特异性 pMHC。我们通过以下两个目标完成这些概念验证研究：(1) 优化 CAR-细菌与 HLA-A2-E7 的结合和特异性，以及 (2) 检查 CAR-细菌在动物模型中的功效头颈癌和宫颈癌。