The field of cancer therapy is rapidly evolving. From nanoparticles designed to carry drugs into the heart of tumours to immune cells engineered with chimeric antigen receptors, novel advancements are being made in the field each year in attempts to combat one of the deadliest afflictions in the developed world. In Canada alone, over 200,000 individuals are diagnosed with cancer each year, and nearly 80,000 Canadians succumb to disease. Close family members of my own are among those battling the illness. It is statistics like this that fuel the constant and tireless search for new and more effective methods of cancer treatment, as most existing standard therapies do not effectively treat disease, or have debilitating side effects that risks or worsens the patient’s quality of life.


Salmonella. Photo credit: Public Health Image Library (PHIL)

One such area of cancer research currently being intensively investigated is bacterial cancer therapy. This method aims to utilize bacteria to activate and target immune cells directly to tumours, delivering a strong anti-tumour response. Attentive IMMpress readers will remember this topic introduced in an earlier article (Germ Warfare on the Cancer Front by Kieran Manion), but significant advances have been made in the field since that initial mention in this magazine in 2014. In fact, personalized and specifically targeted bacterial therapies may be a reality in the very near future. The therapeutic side of bacterial infection was observed as early as the 1800s with physician Dr. William Coley using a mixture of heat inactivated Streptococcus pyrogenes and Serratia marcescens to treat sarcoma patients, which proved to be quite effective in inducing tumour regression. Although this work showed promising anti-tumour activity, it was still quite dangerous due to the possibility of severe bacterial infection in already ill patients. This drawback, in combination with the advent of radiotherapy emerging as an effective method of cancer treatment, left the field of bacterial cancer therapy largely forgotten. Recently, thanks to major advancements in molecular biology and genome editing, bacterial cancer therapy has seen a major resurgence with many labs demonstrating that modified bacteria may prove to be extremely effective anti-tumour therapeutics.

The promising anti-tumour effects of bacterial cancer therapies have helped to speed up the transition from mouse to human studies. Dr. Rosenburg’s group at the National Cancer Institute have shown that an attenuated strain of Salmonella, VNP20009, was effective in colonizing and replicating within several transplanted tumour models. Originally intended as a method of drug delivery to the tumour microenvironment, VNP20009 was able to effectively inhibit the growth of tumours in mice through the induction of pro-inflammatory molecules such as TNF-α which promotes anti-tumour responses. These exciting findings lead to a phase I clinical trial in humans, in which VNP20009 was safely administered to melanoma and renal cell sarcoma patients and able to effectively colonize tumours. In another case, another attenuated strain of Salmonella (AR-1) was able to inhibit the growth of a variety of tumour models in mice, such as pancreatic and breast tumours, as well as force cells into the cell cycle, rendering them sensitive to chemotherapy. While there have certainly been successes, there are still major issues of efficacy and safety plaguing the field. Many bacterial therapeutics still fail to exhibit broad anti-tumour activity over a wide variety of different tumour types and humanized models, until very recently. Dr. Jung-Joon Min’s group based in South Korea has recently published a string of papers in which they report a genetically-modified bacterium with extremely effective anti-cancer properties. These findings stood out due to the high efficacy of tumour inhibition in a variety of different models, as well as the use of gene-specific knockout mice to examine the mechanisms of action by the bacterium. The implications of these engineered bacteria are enormous in the development of potential broadly acting anti-tumour therapies; as such, the details of these studies are described below.

As with many revolutionary scientific discoveries, breakthroughs often come from unexpected origins. In 2006, Dr. Joon-Haeng Rhee’s group at Chonnan National University in South Korea were looking for a vaccine for the bacterium Vibrio vulnificus which was infecting shellfish on the Korean coastline. As they researched the bacterium, they noticed that one of the protein components of its flagellum (FlaB) was able to induce an incredibly strong immune response.

It just so happens that Dr. Min’s group at this university was researching new cancer fighting agents, specifically in the area of bacterial cancer therapy. They decided to focus on Salmonella, which has been shown by many groups to prefer colonization of oxygen-depleted tissues, making them perfect for targeting to the hypoxic tumour microenvironment. Salmonella is a gram-negative, rod-shaped bacterium that is one of the most frequently isolated foodborne pathogens. Salmonella infection remains a significant public health concern, with some strains of the bacterium contributing to significant morbidity and mortality worldwide. Attenuated bacteria have previously shown to be promising anti-cancer therapeutics. The group utilized an attenuated strain of Salmonella typhimurium which demonstrated reduced virulence yet still displayed strong immunogenicity to create a new cancer fighting bacterium. They engineered a plasmid carrying the Vibrio vulnificus FlaB protein under inducible control by L-arabinose and transfected it into their attenuated Salmonella strain. In this way researchers could control the expression of FlaB through the injection of L-arabinose, a 5 carbon sugar, directly into tumours. The inducible control of FlaB helped to give their bacterium safety, allowing the researchers to withhold expression until the bacteria had localized to the tumour environment.

…[T]hanks to major advancements in molecular biology and genome editing, bacterial cancer therapy has seen a major resurgence with many labs demonstrating that modified bacteria may prove to be extremely effective anti-tumour therapeutics.”

After ensuring their bacterium was viable and able to efficiently produce FlaB, they set out to test its anti-tumour properties. This is where many anti-cancer bacteria have failed in the past: they may show potential in vitro or in a few specific tumour models but are unable to combat a variety of different tumours to become a viable cancer therapeutic. Fortunately this was not the case. Their bacterium was able to induce strong tumour-suppressive effects in mouse models of melanoma and colon cancer, as well as effectively prevent metastatic spread and inhibit tumour growth of human colon cancer in mice. In addition to anti-tumour efficacy, their engineered bacteria also demonstrated a good safety profile and led to no adverse effects in any of the mouse models tested.

The authors go on to describe an eloquent mechanism of action. The bacterium colonizes the tumour and increases the infiltration of immune cells, such as monocytes and neutrophils, within the tumour microenvironment. The recruited immune cells are in turn activated by the FlaB produced by the bacterium in a TLR5-dependent process, and begin secreting several pro-inflammatory cytokines. This change in cytokine profile is thought to mediate a M2 to M1 shift within the tumour microenvironment, in which cells transition from a more suppressive M2 phenotype which promotes tumour growth, to a more inflammatory M1 phenotype which inhibits tumour growth. This mechanism is in line with recent advances in the literature surrounding cancer therapeutics, in which several groups have reported that TLR-activating agents exhibit several anti-tumour effects and are under investigation as potential tumour immunotherapies. In summary, the work done by Zheng and colleagues illustrates the potential of bacterial cancer therapy as well as provides researchers with a great target for future therapeutics: the immune receptors. Using engineered bacteria to target specific receptors or cytokine profiles as a means of influencing immune cell migration or function may be the foundation of future bacterial based tumour therapies.

Illustration credit: Dario Ferri
Illustration credit: Dario Ferri

References

  1. Cai Z et al. Activation of Toll-Like Receptor 5 on Breast Cancer Cells by Flagellin Suppresses Cell Proliferation and Tumor Growth. Cancer Research, 71(7): 2466–2475 (2011).
  2. Chakraborty S, & Rahman T. The difficulties in cancer treatment. Ecancermedicalscience, 6:ed16 (2012).
  3. Felgner S et al. Bacteria in Cancer Therapy: Renaissance of an Old ConceptInternational Journal of Microbiology, 2016:8451728 (2016).
  4. Toso JF et al. Phase I Study of the Intravenous Administration of Attenuated Salmonella typhimurium to Patients With Metastatic Melanoma. Journal of Clinical Oncology , 20(1): 142–152 (2002).
  5. Yam C et al. Monotherapy with a tumor-targeting mutant of S. typhimurium inhibits liver metastasis in a mouse model of pancreatic cancer. The Journal of Surgical Research, 164(2): 248–255 (2010).
  6. Zheng JH et al. Two-Step Enhanced Cancer Immunotherapy With Engineered Salmonella Typhimurium Secreting Heterologous Flagellin. Sci Transl Med, 9 (376):pii: eaak9537 (2017).

 

 

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Dario Ferri

Dario is a MSc student at the University of Toronto pursuing a project related to defining new mechanisms by which the immune system is altered in patients with systemic lupus erythematosus.
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