Probiotic neoantigen delivery vectors for precision cancer immunotherapy

Affiliations

• Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, USA.
• Department of Biomedical Engineering, Columbia University, New York, NY, USA.
• Department of Biomedical Engineering, Columbia University, New York, NY, USA. td2506@columbia.edu.
• Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. td2506@columbia.edu.
• Data Science Institute, Columbia University, New York, NY, USA. td2506@columbia.edu.
• Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY, USA. na2697@cumc.columbia.edu.
• Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. na2697@cumc.columbia.edu.

PMID:  39415001  DOI: 10.1038/s41586-024-08033-4

Abstract

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo. With emerging evidence that bacteria naturally home in on tumours and modulate antitumour immunity, one promising application is the development of bacterial vectors as precision cancer vaccines. Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity.

微生物系统已被合成用于在体内部署治疗载荷。有新证据表明，细菌会自然聚集在肿瘤周围，并调节抗肿瘤免疫，因此开发细菌载体作为精准癌症疫苗是一项很有前景的应用。在这里，我们将益生菌Escherichia coli Nissle 1917作为抗肿瘤疫苗接种平台进行了优化，以提高含新表皮肽阵列的生产和细胞递送，并增加血液清除和吞噬的敏感性。这些特点提高了安全性和免疫原性，使该系统能产生强效和特异性 T 细胞介导的抗癌免疫，从而有效控制或消除肿瘤生长，延长晚期小鼠原发性和转移性实体瘤的生存期。我们证明，诱导的抗肿瘤免疫反应包括树突状细胞的招募和激活、新抗原特异性 CD4+ 和 CD8+ T 细胞的广泛引诱和激活、T 细胞和自然杀伤细胞的更广泛激活，以及肿瘤浸润性免疫抑制性髓细胞和调节性 T 细胞及 B 细胞群的减少。总之，这项研究利用活体药物的优势，在最佳环境下提供肿瘤特异性新抗原衍生表位阵列，诱导特异、有效和持久的全身抗肿瘤免疫。

关键词：益生菌，Escherichia coli Nissle 1917，Nissle1917，抗肿瘤免疫