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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.

项目总结