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Tumour-targeting bacteria engineered to fight cancer

Nature Reviews Cancer volume 18, pages 727–743 (2018)Cite this article

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Abstract

Recent advances in targeted therapy and immunotherapy have once again raised the hope that a cure might be within reach for many cancer types. Yet, most late-stage cancers are either insensitive to the therapies to begin with or develop resistance later. Therapy with live tumour-targeting bacteria provides a unique option to meet these challenges. Compared with most other therapeutics, the effectiveness of tumour-targeting bacteria is not directly affected by the ‘genetic makeup’ of a tumour. Bacteria initiate their direct antitumour effects from deep within the tumour, followed by innate and adaptive antitumour immune responses. As microscopic ‘robotic factories’, bacterial vectors can be reprogrammed following simple genetic rules or sophisticated synthetic bioengineering principles to produce and deliver anticancer agents on the basis of clinical needs. Therapeutic approaches using live tumour-targeting bacteria can either be applied as a monotherapy or complement other anticancer therapies to achieve better clinical outcomes. In this Review, we summarize the potential benefits and challenges of this approach. We discuss how live bacteria selectively induce tumour regression and provide examples to illustrate different ways to engineer bacteria for improved safety and efficacy. Finally, we share our experience and insights on oncology clinical trials with tumour-targeting bacteria, including a discussion of the regulatory issues.

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Fig. 1: Mechanisms of tumour cell death by tumour-targeting bacteria.
Fig. 2: Inducible systems used for targeted colonization and payload expression.
Fig. 3: A gene circuit for a transcriptional programme regulating bacterial activities at the population level.

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Acknowledgements

This work was supported by The Virginia and D.K. Ludwig Fund for Cancer Research (S.Z.), BioMed Valley Discoveries, Inc. (S.Z.), Pancreatic Cancer Action Network grant PCAN-422247 (C.G.) and US National Institutes of Health (NIH) grants CA062924 (S.Z.), CA199010 (C.G.) and GM098207 (D.B.).

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Nature Reviews Cancer thanks N. Forbes, J.-J. Min and D. A. Saltzman for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Shibin Zhou

  2. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

    Claudia Gravekamp

  3. Department of Biology, California State University, Northridge, CA, USA

    David Bermudes

  4. Oncology Branch, Division of Clinical Evaluation, Pharmacology and Toxicology; Office of Tissues and Advanced Therapies, CBER, FDA, Silver Spring, MD, USA

    Ke Liu

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  1. Shibin Zhou
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Contributions

S.Z., C.G., D.B. and K.L. researched data for the article, wrote the manuscript and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Shibin Zhou.

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Competing interests

S.Z. is entitled to a share of royalties received by John Hopkins University on sales of products described in this article under a licensing agreement between BioMed Valley Discoveries, Inc. and the university. S.Z. is also a Founding Scientific Adviser of Personal Genome Diagnostics, Inc. and a Founder of PapGene, Inc., which are companies focused on developing genetics-based cancer diagnostics. The terms of these arrangements are under ongoing management by the Johns Hopkins University in accordance with its conflict of interest policies. D.B. has financial interest in Aviex Technologies and Magna Therapeutics and receives royalties from Yale University for technologies based on those described in this article. C.G. has financial interest in Matter Biosciences. K.L. declares no competing interests.

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Glossary

Obligate anaerobes

Microorganisms that cannot survive in the presence of normal atmospheric concentrations of oxygen.

Facultative anaerobes

Microorganisms that can grow in both the presence and the absence of normal atmospheric concentrations of oxygen.

Germinated Clostridium spp.

Vegetative form of clostridia germinated from clostridial spores.

Exotoxin

A bacterial toxin secreted into the surroundings.

Gram-negative bacteria

Bacteria including Salmonella spp. that are unable to retain the crystal violet stain used in the Gram-staining method for bacterial differentiation owing to only a thin layer of peptidoglycan in their cell walls.

Gram-negative sepsis

A life-threatening complication associated with infection by a Gram-negative bacterium triggering systemic inflammatory responses that can lead to tissue damage and organ failure.

Auxotrophic mutation

A mutation that makes an additional nutritional requirement for the growth of the affected bacterium.

Adhesins

Cell surface-exposed bacterial molecules that facilitate adhesion to other cells or surfaces.

Promoter traps

Experimental approaches using reporter activity as the readout to identify particular promoters in a genome by screening libraries constructed with a promoterless reporter gene randomly integrated in the genome or random genomic DNA fragments cloned upstream of a promoterless reporter gene.

Bystander effect

In this context, a therapeutic effect on cells that are not infected by bacteria.

Antigen spreading

Also known as epitope spreading; the expansion of an immune response to antigens that are not the original antigen targeted in the therapy.

Natural killer T cells

(NKT cells). A heterogeneous population of T cells that express an invariant αβ T cell receptor and a number of cell surface molecules typically associated with natural killer cells.

Quorum sensing

A bacterial cell–cell communication process that regulates gene expression in response to fluctuations in population density.

Horizontal gene transfer

The transmission of genetic material between different organisms.

Axenicity

The state of a pure culture of microorganisms, entirely free of all other contaminating organisms.

Angiography

A procedure that uses radiography to examine blood vessels.

Diverticulitis

Inflammation or infection of the small pouches called diverticula formed in the lining of the digestive system.

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Zhou, S., Gravekamp, C., Bermudes, D. et al. Tumour-targeting bacteria engineered to fight cancer. Nat Rev Cancer 18, 727–743 (2018). https://doi.org/10.1038/s41568-018-0070-z

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