Immunotherapies have dramatically improved outcomes for patients with cancer, but some patient populations, such as a large subset of individuals with colorectal cancer, respond poorly to these treatments. However, a potential way to boost these therapies lies with an unexpected source: the foodborne pathogen Listeria monocytogenes.
In a new study in mice, researchers found that ingestion of attenuated L. monocytogenes as an oral cancer vaccine elicited a cytotoxic T cell response in the gut and transiently halted colorectal tumor growth.1 Co-administration of immune checkpoint inhibitors sustained this effect, highlighting a potential new path to harnessing the immune system against these deadly cancers.
An Oral Vaccine Route for a Foodborne Pathogen-Based Therapy
Prior L. monocytogenes-based vaccines were delivered intravenously to help them bypass the body’s natural defenses, but this route can lead to sepsis on rare occasions since the bacteria get delivered directly into the bloodstream.2 The oral vaccine route, on the other hand, impressed Laurence Wood, an immunologist at Texas Tech University who was not involved in the study and who had previously developed an intravenous L. monocytogenes-based vaccine.3
“The natural route of infection for Listeria is foodborne, so it makes sense to leverage that aspect of it,” Wood said. “I think it’s promising that it looks like work is going in this way.”
Study coauthor Semir Beyaz, a cancer biologist at Cold Spring Harbor Laboratory, added, “We think that it’s safer than what’s currently being used in clinical trials for Listeria.”
Researchers develop cancer vaccines using L. monocytogenes because the bacteria contain the protein internalin A, which binds to human E-cadherin, a protein that is often upregulated in tumors.4 This allows L. monocytogenes to invade the cancer cells, and the bacteria’s presence calls immune cells to previously poorly immunogenic tumors.
To test an L. monocytogenes-based vaccine in mice, the researchers first mutated it so that it could interact with the mouse E-cadherin protein. They then inoculated a piece of bread with the unattenuated bacteria and fed it to mice. For comparison, the researchers also administered L. monocytogenes to the animals intravenously.
Oral administration of L. monocytogenes induced T cells to take up residence in the intestinal mucosa significantly more than when the bacteria were delivered intravenously. Residency is an important characteristic for conferring rapid immune response in the organ. The population of resident T cells remained high over three months after infection, demonstrating that orally administered L. monocytogenes could indeed produce a robust immune response.
To make the vaccine safe, the team deleted genes associated with L. monocytogenes pathogenicity. The number of attenuated bacteria in the mouse intestine was comparable to the bacteria’s unattenuated counterparts. However, attenuated L. monocytogenes was hardly detectable in other organs, such as the spleen and liver, demonstrating that the bacteria stayed local and within the target organ, which suggested a lower risk for sepsis. Like their unattenuated counterparts, attenuated L. monocytogenes also induced T cell residency in the intestinal mucosa. Altogether, these results suggest that the vaccine with attenuated bacteria is safe in mice.
A Listeria-Immune Checkpoint Inhibitor Combo Targets Colon Cancer
Next, the researchers evaluated the oral vaccine’s impact on cancer. The team implanted a mouse colon cancer cell line into the colon’s lining 10 days after immunization with attenuated L. monocytogenes. Nearly all the vaccinated mice's tumors shrank within a week after they were immunized. This contrasted with their sham-immunized counterparts, whose tumors grew significantly in that period.
The researchers also tested the vaccine’s therapeutic potential. To do this, they immunized the animals a week before transplanting tumor organoids into their colons. Similarly, this approach considerably halted tumor growth compared to the control groups, but the suppression didn’t last and hardly improved survival. The team hypothesized that the activated T cells might have activated immune checkpoints, which in turn, dampened the resulting immune response. So, starting five days after immunization, the researchers also treated the mice with immune checkpoint inhibitors every other day for two weeks. Compared with either the vaccine or inhibitor treatment alone, the combination therapy significantly suppressed mouse tumor growth for nearly 40 days.
Wood wondered whether the bread that the mice ate conferred L. monocytogenes protection so that it could survive the passage through the digestive tract. He didn’t think it would be a good idea to have people eat Listeria-contaminated food even if the bacteria were attenuated. To him, the approach the researchers used “doesn’t seem like it’s easily translatable.” Wood added, “I wouldn’t give it in bread because then you’re getting it also in your mouth,” suggesting more traditional oral formulation such as capsules.
But Beyaz and his team are optimistic. They hope that their work may lay the foundation for future clinical trials. “[This study] is a good proof of principle to show how you can use a Listeria vaccine to turn an incurable form of colon cancer in combination with immunotherapy,” said Beyaz. “That’s what I’m really excited about.”
- Lei X, et al. Oral immunization with Listeria monocytogenes vaccine enhances immunotherapy for protective immunity in murine models of colorectal cancer. J Immunother Cancer. 2026;14(2):e011570.
- Sacco JJ, et al. Systemic listeriosis following vaccination with the attenuated Listeria monocytogenes therapeutic vaccine, ADXS11-001. Hum Vaccin Immunother. 2016;12(4):1085-1086.
