Probiotic guided CAR-T therapy (ProCARs) for breast cancer

益生菌引导的乳腺癌 CAR-T 疗法 (ProCAR)

基本信息

批准号：
10447144
负责人：
Tal Danino
金额：
$ 67.69万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447144
关键词：
3-Dimensional 4T1 Address Adherent Culture Antibody Therapy Antigen Targeting Antitumor Response Area Automobile Driving Bacteria Binding Breast Cancer Model Breast Cancer therapy CAR T cell therapy CD47 gene Cell Adhesion Molecules Cell Therapy Cells Clinical Trials Coculture Techniques Collagen Communities Cytolysis Cytotoxic T-Lymphocytes Data Development Engineered Probiotics Engineering Environment Escherichia coli Euthanasia Expert Systems Extracellular Matrix Proteins Face Foundations Functional disorder Genetic Genetic Engineering Green Fluorescent Proteins Growth Hematologic Neoplasms Histologic Home Homing Immunologic Adjuvants Immunologic Surveillance In Vitro Individual Infiltration Intelligence Interleukin-12 Lymphoma Malignant Neoplasms Mammary Neoplasms Measurement Medicine Microbe Mind Modeling Molecular Mus Necrosis Neoplasm Metastasis Organ Primary Neoplasm Probiotics Recombinants Safety Solid Solid Neoplasm Specificity Synthetic Antigens System T cell response T cell therapy T-Lymphocyte Technology Testing Therapeutic Time Treatment Efficacy Tumor Antigens Tumor Tissue Tumor-infiltrating immune cells Viral Xenograft procedure base cancer therapy chemokine chimeric antigen receptor chimeric antigen receptor T cells community living cytokine cytotoxicity delivery vehicle dimer draining lymph node engineered T cells imaging system immune stimulant immunoengineering improved in vivo imaging system innovation microbiome monolayer mouse model nanobodies novel novel strategies programmed cell death ligand 1 programs safety testing success synthetic biology tool trafficking transcriptomics triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

PROJECT SUMMARY The engineering of immune cells such as chimeric antigen receptor (CAR)-T cells is driving a new era of cancer therapy. What makes this approach transformative is the ability to genetically program living cells to intelligently sense and respond to environments, adding specificity and efficacy that is not possible to obtain with molecular and antibody-based therapeutics. While CAR-T cell therapy has demonstrated remarkable success for hemato- logical malignancies, it has been faced with many challenges in solid tumor treatment including limitations in targeting safe tumor antigens, poor infiltration into tumors, and increased T cell dysfunction in the suppressive tumor microenvironment. Thus, there is a pressing need to develop technologies to enhance the safety and efficacy of this promising approach for solid tumors. Over the last few decades, microbiome and mechanistic studies have elucidated that bacteria selectively colonize tumor necrotic cores due to reduced immune surveil- lance. Where CAR-T cells struggle to target, locate, and infiltrate solid tumors, bacteria naturally home to, colo- nize, and remain indifferent to the antigenic profile of tumors. Due to advances in engineering capabilities from synthetic biology, microbes represent a natural platform for development as 'smart’ therapeutic delivery vehicles for cancer. In this way, probiotics can infiltrate tumors and be engineered as beacons for directing and enhancing CAR-T cell activities. This project proposal seeks to engineer a bridge between these two complimentary forms of cellular therapies for the treatment of triple negative breast cancer (TNBC). The objective of this proposal is to engineer bacteria and CAR-T cells together, developing a ProCAR (probiotic guided CAR-T cell) system that will improve the limitation of individual agents. Specifically, probiotics will be engineered to home to tumors and locally produce immune-stimulants to enhance CAR-T cell therapies – while CAR-T cells will be engineered to sense these molecules. The overarching innovation of this proposal is engineering communities of living medi- cines, where tumor colonizing bacteria are reengineered as beacons for directing and enhancing CAR-T cell cytotoxicity. This will be a fundamentally new approach to genetically engineering interactions between living medicines, combining the advantages of CAR-T cells and tumor-specific bacteria for cancer therapy, and further building the foundation for engineered communities.

项目概要嵌合抗原受体 (CAR)-T 细胞等免疫细胞工程正在推动癌症的新时代使这种方法具有变革性的是能够对活细胞进行智能编程。对环境的感知和响应，增加了分子不可能获得的特异性和功效 CAR-T 细胞疗法在血液治疗方面取得了显着的成功。逻辑恶性肿瘤，实体瘤治疗面临着许多挑战，包括治疗的局限性靶向安全肿瘤抗原、肿瘤浸润不良以及抑制性 T 细胞功能障碍增加因此，迫切需要开发增强安全性和肿瘤微环境的技术。在过去的几十年里，微生物组和机制研究了这种有前景的方法对实体瘤的疗效。研究表明，由于免疫监视减弱，细菌选择性地定植于肿瘤坏死核心。在 CAR-T 细胞难以靶向、定位和渗透实体瘤的地方，细菌自然就栖息于此。由于工程能力的进步合成生物学中，微生物代表了开发“智能”治疗输送工具的天然平台通过这种方式，益生菌可以渗透肿瘤并被设计为引导和增强的信标。该项目提案旨在构建这两种互补形式之间的桥梁。该提案的目的是治疗三阴性乳腺癌（TNBC）的细胞疗法。将细菌和 CAR-T 细胞一起改造，开发 ProCAR（益生菌引导 CAR-T 细胞）系统具体来说，益生菌将被设计为针对肿瘤和本地生产免疫刺激剂以增强 CAR-T 细胞疗法——而 CAR-T 细胞将被设计为该提案的首要创新是构建活体医学社区。电影中，肿瘤定植细菌被重新设计为引导和增强 CAR-T 细胞的信标这将是生物体之间基因工程相互作用的一种全新方法。药物，结合CAR-T细胞和肿瘤特异性细菌的优势进行癌症治疗，并进一步为工程社区奠定基础。