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

项目摘要 嵌合抗原受体（CAR）-T细胞等免疫细胞的工程化正在推动癌症的新时代 疗法使这种方法具有变革性的是通过基因编程活细胞的能力， 对环境的感知和反应，增加了分子生物学不可能获得的特异性和功效， 和基于抗体的疗法。虽然CAR-T细胞疗法在造血干细胞治疗方面取得了显着的成功， 逻辑恶性肿瘤，在实体瘤治疗中面临许多挑战，包括 靶向安全的肿瘤抗原，对肿瘤的浸润较差，以及抑制性免疫中T细胞功能障碍增加。 肿瘤微环境因此，迫切需要开发技术来提高安全性， 这种有前途的方法对实体瘤的有效性。在过去的几十年里，微生物组和机械 研究已经阐明，由于免疫监视减少，细菌选择性地定殖于肿瘤坏死核心， 兰斯在CAR-T细胞难以靶向、定位和浸润实体瘤的地方，细菌自然会以科洛为家。 nize，并保持对肿瘤的抗原谱漠不关心。由于工程能力的进步， 合成生物学，微生物代表了一个天然的平台，发展为'智能'治疗输送车辆 治疗癌症通过这种方式，益生菌可以渗透肿瘤，并被设计为引导和增强肿瘤的信标。 CAR-T细胞活性。本项目建议书旨在设计这两种互补形式之间的桥梁 用于治疗三阴性乳腺癌（TNBC）的细胞疗法。本提案的目的是 将细菌和CAR-T细胞一起工程化，开发ProCAR（益生菌引导的CAR-T细胞）系统， 将改善个体代理人的局限性。具体来说，益生菌将被设计成肿瘤的家园， 局部产生免疫刺激剂以增强CAR-T细胞疗法-而CAR-T细胞将被工程化， 感知这些分子。这项提案的首要创新是设计活的医学社区， 在电影中，肿瘤定植细菌被重新设计为引导和增强CAR-T细胞的信标， 细胞毒这将是一种全新的方法， 药物，结合CAR-T细胞和肿瘤特异性细菌用于癌症治疗的优势，并进一步 为工程化社区奠定基础。

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.