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Sci Transl Med. 2020 Feb 12;12(530). pii: eaax0876. doi: 10.1126/scitranslmed.aax0876.

Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies.

Author information

1
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
2
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
3
Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
4
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA.
5
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. td2506@columbia.edu.
6
Data Science Institute, Columbia University, New York, NY 10027, USA.

Abstract

Checkpoint inhibitors have revolutionized cancer therapy but only work in a subset of patients and can lead to a multitude of toxicities, suggesting the need for more targeted delivery systems. Because of their preferential colonization of tumors, microbes are a natural platform for the local delivery of cancer therapeutics. Here, we engineer a probiotic bacteria system for the controlled production and intratumoral release of nanobodies targeting programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) using a stabilized lysing release mechanism. We used computational modeling coupled with experimental validation of lysis circuit dynamics to determine the optimal genetic circuit parameters for maximal therapeutic efficacy. A single injection of this engineered system demonstrated an enhanced therapeutic response compared to analogous clinically relevant antibodies, resulting in tumor regression in syngeneic mouse models. Supporting the potentiation of a systemic immune response, we observed a relative increase in activated T cells, an abscopal effect, and corresponding increases in systemic T cell memory populations in mice treated with probiotically delivered checkpoint inhibitors. Last, we leveraged the modularity of our platform to achieve enhanced therapeutic efficacy in a poorly immunogenic syngeneic mouse model through effective combinations with a probiotically produced cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). Together, these results demonstrate that our engineered probiotic system bridges synthetic biology and immunology to improve upon checkpoint blockade delivery.

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