Listeria monocytogenes, illustration

Because of their high rates of recurrence even after successful first treatments such as surgery or radiotherapy, colorectal, pancreatic, esophageal, and stomach cancers remain some of the deadliest forms of the disease.

While the success of immunotherapies has provided significant care improvements in some instances—non-small cell lung cancer being perhaps the most notable—researchers have been looking for other methods to stimulate the body’s immune system to fight cancer.

In an effort to improve outcomes for treatment-resistant cancers, a team of investigators at Thomas Jefferson University (TJU) led by Adam Snook, Ph.D., an associate professor of pharmacology and experimental therapeutics, is taking a slightly different approach. In their research, Snook and team are using a combination of two vaccines—one viral and one bacterial—to alert the immune system of the presence of cancer to keep it from flourishing.

The TJU researches showed in an animal model of colorectal cancer that using viral and bacterial vaccine approaches together is safe and far more effective at fighting the cancer than either approach by itself. The first vaccine administered in the study was an adenovirus that Snook is currently testing in Phase II clinical trials that attacks a specific colorectal cancer molecule GUCY2C (pronounced goosey-toosey).

While this has been shown to be highly effective in promoting an immune response in humans, the effect is not long-lasting and when a booster shot of the virus was administered, researchers found that as the body becomes familiar with the adenovirus, the immune response to the additional applications waned.

That led the team to look for an alternate way to boost the immune response, and found it in a modified version of the bacteria Listeria monocytogenes, that doesn’t cause illness I mice or people.

“Listeria has been explored as a vaccine for other conditions. These are mostly cancer, though some work on infectious diseases like HIV has also been explored,” Snook told Inside Precision Medicine. “Interestingly, Listeria has been used mostly to initiate immune responses, rather than boost them.”

In studies conducted in the Snook lab, the team found that Listeria wasn’t very effective at initiating immune responses against cancer, but was very good at boosting responses that were initiated in another way.

“In our case, those responses were initiated with a vaccine based on a chimeric viral vector based on adenovirus,” Snook noted. “The vaccine platforms are not unique, but nobody’s put them together into a combination vaccine, yet that’s when we saw the immune response really take off.”

The approach came to light for the team when it realized that Listeria was an effective means of infecting antigen presenting cells which are known to produce an effective immune response against cancer. With this knowledge, and knowing the adenovirus vaccine produced a strong initial immune response, the researchers hypothesized the two would be effective in combination.

In a model of recurrent colorectal cancer that has spread to parts of the body beyond the colon, the combination vaccine approach reduced metastases and increased survival in the animals. The vaccine strategy also did not produce toxicity or inflammation in the animals indicating that the treatment was well-tolerated without unintended effects.

The findings have laid the groundwork to examine, for the first time, whether this combination could prevent cancers from coming back in patients. The Department of Defense recently awarded Snook, and colleague Babar Bashir, MD, an assistant professor of medical oncology at TJU, a “Team Science” grant to take the combination vaccine approach into a Phase I clinical trial. The researchers are working to manufacture the vaccine now and expect to begin enrolling patients next year.

“The current study showed that Listeria was effective at boosting those responses in mice. Therefore, we plan to first administer adenoviral vaccine to the patients and then give two administrations of the Listeria vaccine, expecting that each Listeria administration will boost immune responses,” Snook added.

While the study was in colorectal cancer, Snook said the approach could also be applied to other cancers, if proven effective.

“The current paper focuses on colorectal cancer. However, we have found that the vaccine target is also made in cancers of the esophagus, stomach, and pancreas. So our combination vaccine could be directly applied to those,” he concluded. “Beyond that, the concept of using adenovirus and listeria together to target other molecules in cancer could be applied to many different cancer types.”

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