Department of Biomedical Engineering, Columbia University, New York, NY, USA.
Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Nat Med. 2019 Jul;25(7):1057-1063. doi: 10.1038/s41591-019-0498-z. Epub 2019 Jul 3.
Synthetic biology is driving a new era of medicine through the genetic programming of living cells. This transformative approach allows for the creation of engineered systems that intelligently sense and respond to diverse environments, ultimately adding specificity and efficacy that extends beyond the capabilities of molecular-based therapeutics. One particular area of focus has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo. Here we engineered a non-pathogenic Escherichia coli strain to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb), an anti-phagocytic receptor that is commonly overexpressed in several human cancer types. We show that delivery of CD47nb by tumor-colonizing bacteria increases activation of tumor-infiltrating T cells, stimulates rapid tumor regression, prevents metastasis and leads to long-term survival in a syngeneic tumor model in mice. Moreover, we report that local injection of CD47nb-expressing bacteria stimulates systemic tumor-antigen-specific immune responses that reduce the growth of untreated tumors, providing proof-of-concept for an abscopal effect induced by an engineered bacterial immunotherapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.
合成生物学通过对活细胞进行基因编程，正在推动医学的新时代。这种变革性的方法允许创建智能感知和响应各种环境的工程系统，最终在特异性和疗效方面超越了基于分子的治疗方法。一个特别关注的领域是将细菌工程化为治疗性药物传递系统，以在体内选择性地释放治疗性有效载荷。在这里，我们设计了一种非致病性大肠杆菌菌株，使其能够在肿瘤微环境中特异性裂解并释放编码的 CD47 纳米体拮抗剂（CD47nb），CD47 是一种在几种人类癌症中普遍过表达的抗吞噬受体。我们发现，肿瘤定植细菌传递的 CD47nb 可增加肿瘤浸润 T 细胞的激活，刺激肿瘤快速消退，防止转移，并在小鼠的同源肿瘤模型中实现长期存活。此外，我们报告说，表达 CD47nb 的细菌的局部注射可刺激全身性肿瘤抗原特异性免疫反应，从而减少未治疗肿瘤的生长，为工程细菌免疫疗法诱导的远隔效应提供了概念验证。因此，工程细菌可用于安全和局部递送免疫治疗有效载荷，从而引发全身性抗肿瘤免疫。
