A new strategy to fight colorectal cancer is showing promise, utilizing a modified version of the bacterium Listeria monocytogenes delivered orally as a vaccine. Researchers have engineered the bacterium to stimulate the immune system directly within the gut, where it can generate anti-tumor cells, offering a potentially more targeted approach than traditional cancer immunotherapies. This research, focused on an oral vaccine for colorectal cancer, represents a significant step forward in the field of cancer immunotherapy.
Colorectal cancer remains a major global health challenge. The American Cancer Society projects more than 150,000 new diagnoses and over 55,000 deaths in the United States alone in 2026. Although cancer immunotherapy—harnessing the body’s own immune system to fight cancer—has shown success in some cases, it’s currently effective for only a small proportion of colorectal cancer patients. Many colorectal cancers prove unresponsive to existing immunotherapies, highlighting the require for innovative approaches like this new vaccine strategy.
Engineering Listeria for Targeted Immunity
The research, led by Brian Sheridan, associate professor in the microbiology and immunology department at Stony Brook University’s Renaissance School of Medicine, builds on the existing understanding of Listeria monocytogenes as a potential immunotherapy agent. Listeria, while capable of causing infection, has been investigated in pre-clinical and clinical trials for its ability to stimulate an immune response against cancer cells. However, previous Listeria-based vaccines were typically administered intravenously.
Sheridan and his team took a different approach, focusing on oral delivery. They engineered a highly attenuated strain of the bacterium, removing key genes responsible for causing illness—specifically the ActA and InlB virulence genes—while preserving its ability to access the intestinal immune system. This modification allows the vaccine to stimulate an anti-tumor response without causing listeriosis, a foodborne illness. The engineered strain also contains an internalin A mutation (InlAM) that allows for epithelial cell invasion.
Promising Results in Murine Models
The team tested their oral vaccine in mouse models of colorectal cancer. The results demonstrated that the vaccine remained contained within the intestinal tissues, without spreading to other organs or causing significant side effects like weight loss. This localized approach ensured the immune system reacted specifically to the site of the cancer, minimizing damage to healthy tissues.
In mice proactively immunized with the vaccine, researchers observed protection from developing colorectal tumors. Even more encouragingly, therapeutic immunization—treating mice already bearing tumors—curtailed local tumor growth. However, the most significant gains were seen when the vaccine was combined with existing immune checkpoint inhibitors.
“While this vaccine alone initially curtailed local tumor growth, its true potential was revealed when combined with existing immune checkpoint inhibitors,” Sheridan explained in a press release. “This combination therapy led to profound tumor control in the model and suggests that the vaccine can effectively ‘turn on’ the immune system in tumors that were previously resistant to standard immune therapy.”
Boosting the Immune Response with Combination Therapy
The research further revealed that oral immunization, when coupled with immune checkpoint inhibitors, led to an accumulation of tumor-specific CD8 T cells within the tumor environment. These specialized immune cells, stationed in the gut, provide immediate and long-lasting protection against cancer cells—a response not achieved through vaccination or immune checkpoint inhibitors alone. This accumulation of CD8 T cells is a key indicator of a robust and targeted immune response.
The study utilized two different colorectal cancer models: a microsatellite instability high MC38 cell line expressing ovalbumin, and a genetically engineered microsatellite stable AKPS organoid line also expressing low levels of ovalbumin. The researchers tested the vaccine in both prophylactic (preventative) and therapeutic settings.
Looking Ahead: Clinical Trials and a New Generation of Vaccines
Sheridan emphasizes the potential clinical significance of these findings, suggesting the strategy could significantly improve outcomes for patients with advanced or metastatic colorectal cancer who have limited treatment options. “such a strategy could significantly improve the prognosis for patients with advanced or metastatic colorectal cancer who have limited therapeutic options otherwise,” he said. He also believes this method could pave the way for a new generation of cancer vaccines capable of both preventing disease onset and enhancing the effectiveness of existing immunotherapies.
The research was supported by funding from the Department of Defense, the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID), the Research Foundation for the State University of New York, and several charitable foundations. The next step will involve further pre-clinical studies and, eventually, clinical trials to assess the safety and efficacy of the oral vaccine in humans.
Disclaimer: This article provides information for general knowledge and informational purposes only, and does not constitute medical advice. It is essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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