In the late 19th century, an American bone surgeon named William Coley discovered a surprising pattern: cancer patients who also developed skin infections seemed to be getting better. Reviewing the research, he had found dozens of cases confirming his hunch that bacteria might be involved in tumour regression.
While Coley did not fully understand the mechanism responsible (an immune response), he felt this was an avenue worth pursuing. He began to treat his own cancer patients with streptococcus bacteria, injected straight into the tumour site. Many patients recovered, but others died, prompting Coley to use inactivated bacteria instead.
Today, after many decades in which his ideas went undeveloped, Coley is considered the ‘father of cancer immunotherapy’. And while his treatment was neither safe nor especially effective, ‘Coley’s toxins’ are a precursor to a wave of bacteria-based cancer therapies being explored today.
“His approach died down because while he had some successful cases, he also had cases where it led to a septic shock,” says Dr Simone Schürle-Finke, assistant professor at the Department of Health Sciences and Technology, ETH Zurich.
“We also saw the rise of radiation and chemotherapy. However, this approach is now experiencing a renaissance, because we have the toolkits of synthetic biology and the momentum of immunotherapy in general.”
How might bacteria fight cancer?
Bacteria have several properties that make them viable candidates for cancer treatment. First, they preferentially grow and proliferate within tumour sites, which causes immune cells to infiltrate the tumour and provokes an anti-cancer response.
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“Bacteria have onboard sensing – they can follow chemical cues,” explains Schürle-Finke. “When you inject a drug, it just gets distributed, but bacteria have their own molecular motor mechanism. By sensing hypoxic regions like you have in tumours, they can navigate the region, or at least preferentially amplify in the areas that we actually like to target.”
Some bacteria also produce toxins that may be useful within cancer therapy. These have been tested in animal models with some degree of success. However, researchers following in Coley’s footsteps have not been able to make much headway using bacterial strains alone.
On top of that, the fact remains that bacterial injections can be dangerous, for exactly the same reasons that applied in Coley’s day. If bacteria are left to proliferate, the body can mount a heightened immune response that progresses to septic shock.
Additionally, some bacteria are themselves involved within the progression of cancer and can even cause resistance to chemotherapy drugs.
Synthetic biology approaches
For that reason, a number of researchers are now turning to synthetic biology to improve the efficacy of these treatments and minimise the risks. Following the advent of genetic engineering approaches like CRISPR, bacteria can now be programmed to release anticancer compounds at the tumour site.
“Bacteria can already have innate toxins, but now they can also be genetically modified for certain drug production and release,” says Schürle-Finke. “This is a magic bullet in a sense – you have an amplification of the drug dose at the target.”
They can also be engineered for other characteristics desirable within cancer therapy – for instance, producing molecules that heighten the immune response, or self-destructing once they reach a critical mass.
“There’s some kind of additional intelligence that can be encoded by genetic circuits, which make bacteria-based therapies more safe, more targeted, more selective,” says Schürle-Finke.
“My colleague Tal Denino [assistant professor of biomedical engineering at Columbia University] just had a paper published in Nature Biomedical Engineering, which showed that bacteria could be programmed with genetic circuits that sense certain environmental triggers. If the trigger is there, the toxin is released.”
Mechanical engineering approaches
Schürle-Finke’s research follows more of a mechanical engineering approach. She has been developing microscopic propellors based on bacteria, for use within targeted drug delivery.
The main application here will be in nanoparticle-based therapies. While nanoparticles hold great promise within cancer treatment (often in the form of tiny capsules that release the drug under certain triggers), the particles can often get lost within the body. Less than 1% of the injected dose, on average, actually reaches the tumour site.
“There’s interest in helping the targeting and guidance of these nano drug carriers to the disease site,” says Schürle-Finke. “I’ve been working on a magnetic intravascular propeller inspired by bacterial flagella, which have developed an advantageous mechanism for propulsion at the small scale.
“I also found naturally existing magnetic bacteria – I’ve been culturing them and showing that, by harnessing their magnetic field, you can get very powerful swarm control and use that to move nanoparticles.”
This thinking might be extended to bacteria-based therapies. After all, if a higher proportion of bacteria reach the tumour, you can lower the treatment dose.
“There are some bacteria that we can tolerate fairly well in the bloodstream, but only at very low doses,” she says.
“Because the lower dose is not so aggressive in penetrating tumours, we could modify them with magnetic material or use control strategies that selectively enhance their transport towards the envisioned area. You get a carefully curated immune response, rather than a systemic shock.”
Another line of enquiry lies in modulating the microbiome to improve the patient’s defences against cancer. We know that certain cancers are linked to certain gut bacteria. Following that logic, some researchers are enlisting predatory bacteria in the fight against the cancer-causing microbes.
Possible directions for the future
So when might bacterial-based therapies for cancer hit the mainstream? Although some applications may sound quite speculative, a number of biotech companies are betting big on their potential, and clinical trials are underway across many different types of bacteriotherapy.
“There are cases where intratumoral bacterial injection is a really good solution,” says Schürle-Finke.
“The next steps are how we can move to controlled intravenous injection – meaning into the bloodstream rather than locally into the tumour – and how we can address metastasis. I hope that intravenous injection will be approved within the next three to five years, depending on how fast we’re all progressing.”
It is unlikely that these therapies, in most cases, would be deployed instead of existing treatments. Rather, they would be used in conjunction with radiotherapy or chemotherapy as part of a combination therapy.
As engineering approaches become more sophisticated, and the safety challenges are overcome, bacteria could prove to be a powerful ‘living medicine’ and an important tool in our armoury – giving a new lease of life to William Coley’s ideas.