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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.

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Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10027, USA.
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Data Science Institute, Columbia University, New York, NY 10027, USA.


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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