Research ArticleCancer

Engineered probiotics for local tumor delivery of checkpoint blockade nanobodies

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Science Translational Medicine  12 Feb 2020:
Vol. 12, Issue 530, eaax0876
DOI: 10.1126/scitranslmed.aax0876

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Bacterial helpers to the rescue

Immune checkpoint inhibitors are a promising and increasingly popular approach to cancer therapy. Unfortunately, they sometimes have severe immune-mediated side effects, which can be minimized by local delivery of immunotherapy to the tumors. To address this problem, Gurbatri et al. engineered a probiotic bacteria system to release nanobodies targeting the immune checkpoints. After the bacteria were injected into a tumor, they stimulated a systemic antitumor immune response, successfully attacking not only the injected tumor but also any others found in the body. They could also be engineered to express an immunostimulatory cytokine to further boost the antitumor response in less immunogenic tumors.

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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