Cancer immunotherapies have transformed treatment for many cancers, but pancreatic cancer remains especially difficult to treat.

One major reason is that pancreatic tumours often create a “cold” tumour microenvironment, where the tumour prevents immune cells from mounting a strong attack.

In a new study published in Science Advances, researchers at the University of Chicago report a promising new strategy to overcome this barrier using BifidoSumIL-2, an engineered bacterial strain of Bifidobacterium longum, a probiotic bacterium naturally found in the gut, to deliver an immune-stimulating therapy directly inside tumours.

The treatment suppressed pancreatic tumour growth by selectively activating cancer-fighting T cells.

The effects were further enhanced when combined with chemotherapy, radiotherapy or immunotherapy.

The study highlights BifidoSumIL-2 as a potentially powerful approach for improving treatment response in pancreatic cancer.

A novel bacterial delivery strategy

“A big unmet medical need has been pancreatic cancer, and so that was going to be our mountain to climb,” said Ralph Weichselbaum, MD, the Daniel K. Ludwig Distinguished Service Professor and Chair of Radiation and Cellular Oncology at the University of Chicago.

The new therapy, called BifidoSumIL-2, is designed to release a modified form of interleukin-2 (IL-2) inside tumours.

IL-2 is a powerful immune molecule that activates T cells, which help the body fight cancer.

However, traditional IL-2 therapy can cause harmful side effects and may also activate immune cells that suppress the antitumor response.

To address this, the team used SumIL-2, an engineered version of IL-2 designed to more selectively stimulate cancer-fighting T cells while limiting activation of regulatory T cells.

By placing SumIL-2 inside Bifidobacterium longum, the researchers aimed to concentrate the treatment directly within tumours.

The work required expertise across multiple fields, from microbiology and synthetic biology to oncology and immunology.

“This was a highly interdisciplinary effort,” said Mark Mimee, PhD, Assistant Professor of Microbiology at the University of Chicago.

“We had to bring together people who understand bacteria, people who understand tumours, and people who understand the immune system to make something like this possible.”

Engineering the bacteria

Bifidobacterium was an attractive delivery vehicle because it thrives in anaerobic environments, meaning low-oxygen environments, a common feature of many solid tumours, including pancreatic tumours.

Healthy tissues generally have higher oxygen levels, making them less favourable for bacterial growth.

“Bifidobacterium is an obligate anaerobe, so it doesn’t grow in the presence of oxygen,” Mimee said.

After systemic injection, the bacteria are cleared from oxygen-rich healthy tissues but can become active in the low-oxygen regions of tumours.

This tumour-seeking behaviour allows the bacteria to act like microscopic drug factories.

Essentially, these little factories produce the SumIL-2 only on the tumour site where the drug is needed.

The researchers noted that Bifidobacterium has a favourable safety profile in preclinical models and is already widely recognised as a probiotic organism.

It is commonly found in yoghourt, so it is generally recognised as a safe, off-the-shelf probiotic.

“Bifidobacterium is not the easiest organism to work with,” Mimee said.

“It’s anaerobic, it grows slowly, and the genetic tools for manipulating it are much more limited compared to model bacteria like E. coli. A lot of the work was just figuring out how to reliably engineer it.”

Enhanced effects with combination therapy

In animal models, BifidoSumIL-2 selectively accumulated in tumours, activated immune responses, and slowed pancreatic tumour growth.

The treatment also helped reshape the tumour microenvironment by increasing the activity of cancer-fighting CD8+ T cells.

The therapy became even more effective when combined with standard cancer treatments.

Pairing BifidoSumIL-2 with chemotherapy, radiation therapy, or anti-PD-L1 immunotherapy further improved tumour control and survival compared with single treatments alone.

“This combination potential is one of the study’s most important findings; BifidoSumIL-2 not only works by itself — it works with radiotherapy, chemotherapy, and immunotherapy," Weichselbaum said.

Although the results are promising, BifidoSumIL-2 has not yet been tested in people.

Future studies will need to evaluate long-term safety, possible off-target effects, durability of the immune response, and whether the bacteria can be delivered orally rather than by injection.

Researchers are also interested in combining this approach with newer pancreatic cancer therapies, including KRAS inhibitors.

The study highlights a growing “bugs as drugs” strategy, in which engineered probiotic bacteria could provide a new way to deliver immune therapies directly into hard-to-treat tumours while limiting side effects elsewhere in the body.

The study, “Engineered probiotic Bifidobacterium for tumour-targeted pancreatic cancer therapy” was supported by funds from the Ludwig Foundation and the National Institutes of Health.

Additional authors include Jaehyun Lee, Kaiting Yang, Christina Nowicki, Wei Liu, , Emile Naccasha, and Hua Liang from the University of Chicago; Zhichen Sun from the University of Texas Southwestern, Dallas; and Yang-Xin Fu from the Tsinghua University, Beijing, China.

Source: University of Chicago Medical Center