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

项目总结 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纪元 心理治疗。这种方法之所以具有变革性，是因为它能够从基因上对活细胞进行编程，以智能地 感知和响应环境，增加了分子无法获得的特异性和有效性 以及基于抗体的疗法。虽然CAR-T细胞疗法在治疗血液病方面取得了显著的成功。 逻辑恶性肿瘤，它在实体肿瘤治疗中面临着许多挑战，包括限制在 靶向安全的肿瘤抗原，肿瘤侵袭能力差，抑制性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增强安全和 这一有希望的方法对实体肿瘤的疗效。在过去的几十年里，微生物组和机械学 研究已经阐明，由于免疫监视减少，细菌选择性地定植于肿瘤坏死核心。 兰斯。在CAR-T细胞努力靶向、定位和渗透实体肿瘤的地方，细菌天然地聚集在科罗拉多州。 保持对肿瘤抗原性的漠视。由于工程能力的进步，从 合成生物学，微生物代表着一个天然的平台，可以发展为“智能”的治疗载体 治疗癌症。通过这种方式，益生菌可以渗透到肿瘤中，并被设计为引导和增强的灯塔 CAR-T细胞活动。该项目提案试图在这两种免费形式之间架起一座桥梁 用于治疗三阴性乳腺癌(TNBC)的细胞疗法。这项提议的目标是 将细菌和CAR-T细胞结合在一起，开发一种Procar(益生菌引导的CAR-T细胞)系统， 将改善对个人代理人的限制。具体地说，益生菌将被改造成肿瘤和 当地生产免疫兴奋剂以增强CAR-T细胞疗法-而CAR-T细胞将被改造成 感觉这些分子。这项建议的总体创新是工程社区的生活中- Cines，肿瘤定植细菌被重新设计为引导和增强CAR-T细胞的灯塔 细胞毒性。这将是一种从根本上解决生物之间基因工程相互作用的新方法。 药物，结合CAR-T细胞和肿瘤特异性细菌的优势用于癌症治疗，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.