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Programmable bacteria induce durable tumor regression and systemic antitumor immunity

View ORCID ProfileSreyan Chowdhury, Taylor E. Hinchliffe, Samuel Castro, Courtney Coker, View ORCID ProfileNicholas Arpaia, View ORCID ProfileTal Danino
doi: https://doi.org/10.1101/561159
Sreyan Chowdhury
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
2Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
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Taylor E. Hinchliffe
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
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Samuel Castro
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
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Courtney Coker
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
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Nicholas Arpaia
2Department of Microbiology & Immunology, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
3Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
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Tal Danino
1Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
3Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
4Data Science Institute, Columbia University, New York, NY 10027, USA
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SUMMARY PARAGRAPH

Synthetic biology is driving a new era of medicine through the genetic programming of living cells1,2. 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 therapeutics3–5. One particular focus area has been the engineering of bacteria as therapeutic delivery systems to selectively release therapeutic payloads in vivo6–8. Here, we engineered a non-pathogenic E. coli to specifically lyse within the tumor microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb)9, an anti-phagocytic receptor commonly overexpressed in several human cancers10,11. We show that intratumoral 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. Moreover, we report that local injection of CD47nb bacteria stimulates systemic antitumor immune responses that reduce the growth of untreated tumors – providing, to the best of our knowledge, the first demonstration of an abscopal effect induced by a bacteria cancer therapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 01, 2019.
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Programmable bacteria induce durable tumor regression and systemic antitumor immunity
Sreyan Chowdhury, Taylor E. Hinchliffe, Samuel Castro, Courtney Coker, Nicholas Arpaia, Tal Danino
bioRxiv 561159; doi: https://doi.org/10.1101/561159
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Programmable bacteria induce durable tumor regression and systemic antitumor immunity
Sreyan Chowdhury, Taylor E. Hinchliffe, Samuel Castro, Courtney Coker, Nicholas Arpaia, Tal Danino
bioRxiv 561159; doi: https://doi.org/10.1101/561159

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