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：
10263960
负责人：
Tal Danino
金额：
$ 67.51万
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/10263960
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 Immune 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 dimer draining lymph node engineered T cells imaging system 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.

项目摘要诸如嵌合抗原受体（CAR）-T细胞等免疫细胞的工程正在推动癌症的新时代治疗。使这种方法变革的原因是能够遗传对活细胞进行智能编程的能力感知并响应环境，增加了用分子获得的特异性和效率和基于抗体的治疗。虽然CAR-T细胞疗法表现出了出色的成功成功逻辑上的malignancys，在实体瘤治疗中面临许多挑战，包括限制靶向安全的肿瘤抗原，浸润不良成肿瘤，并增加抑制性的T细胞功能障碍肿瘤微环境。这是迫切需要开发技术以提高安全性和这种承诺方法对实体瘤的功效。在过去的几十年中，微生物组和机械研究已经阐明了细菌选择性地定居于肿瘤坏死核，这是由于免疫生育降低而导致的在CAR-T细胞难以靶向，定位和浸润的实体瘤，自然而然的细菌，Colo- nize，并且对肿瘤的抗原谱保持无动于衷。由于工程能力的进步合成生物学，微生物代表了自然的开发平台，作为“智能”热递送车辆用于癌症。这样，益生菌可以渗入肿瘤并被设计为标志以指导和增强 CAR-T细胞活动。该项目提案旨在设计这两种免费形式之间的桥梁用于治疗三重阴性乳腺癌（TNBC）的细胞疗法。该提议的目的是一起设计细菌和CAR-T细胞，开发一个Procar（益生菌引导的CAR-T细胞）系统，该系统将提高各个代理的限制。具体而言，益生菌将被设计为肿瘤和当地产生的免疫刺激剂以增强CAR-T细胞疗法 - 而CAR-T细胞将设计为感觉这些分子。该提案的总体创新是生活中的工程社区 Cines，肿瘤定居细菌被重新设计为用于指导和增强CAR-T细胞的信标细胞毒性。这将是一种从根本上进行基因工程互动的新方法药物，结合了CAR-T细胞和肿瘤特异性细菌在癌症治疗中的优势，并进一步为工程社区建立基础。