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.

抽象的该项目的目的是探索产生嵌合抗原受体（CAR）的可行性由细菌表达。我们建议不使用T细胞，而是建议探索细菌介导的想法和使用癌细胞的目标破坏。此外，我们探讨了我们可以瞄准汽车 - 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） - 氯肽复合物（PMHC）。我们称之为这些工程细菌细胞汽车 - 细菌。当前表达汽车的T细胞提供持久的响应，但具有三个主要局限性：特异性，毒性和可行性。这项研究将解决所有三个问题。在这个提案，我们将工程的细菌裂解靶向头颈或表达HLA-A2-E7的宫颈癌细胞，一种已知的PMHC在被人乳头瘤病毒（HPV）感染的肿瘤细胞上。靶向启用抗肿瘤蛋白仅当达到细菌的预定义人口密度时，生产。此方法应该显着减少细菌菌落的大小，大大降低/可防止全身毒性。该方法有可能成为HPV阳性口腔癌的治疗性，因为它可以作为细菌漱口水进行给药和控制。该项目结合了两项创新，利用合成发展的纳米病（SEN）图书馆证明了能够选择性结合MHC肽复合物并将这种特定的癌细胞靶向与同步的电路裂解以产生汽车 - 细菌。我们提出的研究提供了（1）汽车的概念证明可以产生识别PMHC的产生，（2）可以通过肿瘤控制CAR-细菌定位和定植某些PMHC和（3）CAR细菌的表达具有对表达肿瘤细胞的治疗活性特定PMHC。我们通过以下两个目标完成了这些概念验证研究：（1）优化 CAR-细菌对HLA-A2-E7的结合和特异性和（2）检查动物模型中CAR-细菌的功效头颈和宫颈癌。