Engineered Probiotics Deliver Chemotherapy and Immunotherapy Directly to Colorectal Tumours

Chemotherapy has a precision problem.

It remains one of the most effective treatments for aggressive cancer, yet as it travels around the body it cannot reliably distinguish between the cancer cells it is meant to target and the surrounding healthy tissue.

Immunotherapy has a similar drawback. By directing the immune system to deploy the body’s natural defences against malignant cells, it can also damage healthy tissues, triggering dangerous inflammation and systemic toxicity.

Because cancer arises from the body’s own cells, finding ways to attack tumours without harming healthy tissue has proved one of the greatest challenges in treating the disease in its many forms.

Scientists have now demonstrated a different strategy: converting probiotic bacteria into minute drug factories that establish themselves within tumours, where they manufacture chemotherapy and simultaneously help mobilise the immune system against cancer.

In tests involving mice, the treatment completely eliminated three of seven colorectal tumours.

That is a modest finding, certainly, but it indicates that engineered probiotics might eventually become an important part of the cancer-fighting toolkit.

Colorectal cancer and targeted treatment

Colorectal cancer is among the most frequently diagnosed cancers globally and continues to be a major cause of cancer-related death. While survival rates have improved substantially, advanced disease is still treated largely with chemotherapy, including 5-fluorouracil, or 5-FU.

The search for new treatments is especially urgent as colorectal cancer becomes more common in younger people, for reasons researchers have yet to establish.

One approach receiving increasing attention is delivering treatment straight to the affected tissue, focusing its cancer-killing action where it is required while reducing exposure throughout the rest of the body.

Some of the most promising delivery vehicles are living organisms.

A research team led by Columbia University immunologist Nicholas Arpaia selected Escherichia coli Nissle 1917, a bacterium used as a probiotic to support gut health.

Bacteria possess several characteristics that can make them useful for cancer targeting.

After entering the bloodstream, certain bacteria preferentially gather and reproduce within tumours, whose unusual conditions can offer a comparatively welcoming environment for growth.

Tumour interiors may have little oxygen and plentiful nutrients from dying cells, while the local immune system is suppressed. Such conditions can enable some bacteria to flourish.

As E. coli Nissle 1917 is a well-characterised, non-pathogenic probiotic strain, the scientists thought it could be an effective carrier for cancer therapies.

They first needed to establish whether it would reach the intended location. The team grew colorectal tumours in laboratory mice and injected the animals with the bacteria, which quickly vanished from the major organs.

Tests of the tumours revealed enormous bacterial build-ups: more than a billion bacterial cells per gram of tumour tissue within only five days.

More encouragingly, the bacteria could be programmed to discharge a payload after arriving.

The scientists gave the microbes a synchronised lysis circuit, designed to make them burst once their numbers reached a specified density and release their contents into the surrounding tumour tissue.

The next task was deciding what those microbes should release.

Engineered probiotics manufacture chemotherapy inside tumours

The team modified the bacteria to make an enzyme known as cytosine deaminase. When this enzyme meets the relatively non-toxic compound 5-fluorocytosine, or 5-FC, it converts it into 5-FU, the colorectal cancer chemotherapy drug mentioned above.

The plan was for bacteria to colonise a tumour while the researchers administered 5-FC separately. The prodrug would become the cancer-fighting compound only when it encountered the bacterial enzyme within the tumour.

In principle, this could confine the toxic action of 5-FU to the intended site and limit its effects elsewhere in the body.

In the team’s first experiment, conventional 5-FU slowed tumour growth, but the mice lost around 7 percent of their body weight, an indication of systemic toxicity.

That issue diminished when the bacterial approach was used. However, a different problem appeared.

The therapy barely reduced the tumours at all.

The researchers therefore investigated and identified a major defect in their miniature drug factories: the bacteria were breaking down the chemotherapy they had been designed to make.

E. coli naturally contains genes called preTA, enabling it to degrade 5-FU into a much less toxic compound. Thus, although the engineered bacteria successfully transformed 5-FC into chemotherapy, they were also almost instantly neutralising that chemotherapy.

The scientists removed preTA from their engineered bacteria. This time, the therapy performed considerably better.

Combining chemotherapy with an immune response

However, this exposed another challenge. The localised chemotherapy was activating cancer-fighting immune cells in the tumours, including T cells and natural killer cells.

At the same time, though, the tumours were strengthening their own defences, including greater numbers of regulatory T cells and increased levels of the immune-suppressing protein PD-L1.

The team returned to editing the bacteria. Alongside the payload that converts 5-FC into 5-FU, they engineered the E. coli to manufacture two further compounds: an IL-15 superagonist to spur cancer-fighting immune cells into action, and a nanobody that blocks PD-L1, lifting one of the brakes tumours use to suppress an immune assault.

The resulting microbe delivered a powerful three-part combination: chemotherapy generated directly in the tumour, an immune stimulant and a localised form of immune checkpoint blockade.

This was where the treatment became particularly compelling.

In mice with established colorectal tumours, one injection of the engineered bacteria directly into a tumour, followed by doses of 5-FC, achieved significantly stronger tumour control than either bacterial immunotherapy or bacterial chemotherapy alone.

Three of the seven tumours vanished completely: 43 percent.

There were also indications that the benefits extended beyond the treated tumour. The researchers implanted tumours on both sides of some mice but treated only one side.

The treated tumour responded, but remarkably, the untreated tumour’s growth also slowed substantially. When the team examined the untreated tumour, it found no trace of the engineered bacteria, indicating that the treatment had stimulated a broader immune response against the cancer.

There is, naturally, a considerable distance to travel before this treatment could be used in people. It was a small experimental study in mice with artificially implanted tumours, and much of the testing involved injecting bacteria directly into tumours. That would not necessarily be possible for human patients.

The researchers say subsequent work must assess the method in models that more closely represent the complexity of human cancers, as well as evaluate delivery techniques appropriate for clinical use.

Nevertheless, the demonstration is a promising move towards targeted cancer treatment that combines the complementary advantages of chemotherapy and immunotherapy while potentially lowering their systemic side effects.

"With a deeper understanding of tumor immunology and emerging biomarkers, this system should help advance cancer chemoimmunotherapy by offering a highly adaptable, targeted, and synergistic approach to overcoming tumor heterogeneity, toxicities, and treatment resistance across a variety of cancer types," the researchers write.

The findings were published in Science Translational Medicine.

This article was fact-checked and edited by Rebecca Dyer. Although we take pride in our process, we are only human. If you notice an error, please let us know.