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Mouse Study Sheds Light On Why Some Cancer Vaccines Fail

A simple switch of ingredients made a big difference in how mice responded to experimental cancer vaccines.
Andrei Tchernov
A simple switch of ingredients made a big difference in how mice responded to experimental cancer vaccines.

In the quest for better cancer medicines, vaccines that treat rather than prevent disease are getting lots of attention.

More than 90 clinical trials have tested therapeutic vaccines in cancer patients, but the results have been a mixed bag.

A recent study in mice suggests that changing a traditional ingredient in the vaccines could make a big difference.

A typical therapeutic vaccine against cancer contains a cancer-specific peptide, or protein fragment, that is injected under a patient's skin. The peptide serves as a red flag for the immune system. If all goes well, the patient's immune system recognizes the peptide as something to be attacked and boosts the population of cancer-fighting T-cells in the bloodstream.

For such vaccines to work against the cancers, though, these cells have to find their way to tumors. This migration might not be happening as expected in traditional human cancer vaccines, says Willem Overwijk, an author of the study in the latest Nature Medicine and an assistant professor at MD Anderson Cancer Center in Houston.

Cancer vaccines typically include a substance called IFA, short for "incomplete Freund's adjuvant." Adjuvants are chemicals added to vaccines to stimulate an immune response.

"IFA is a mineral oil that is not biodegradable by the body," says Overwijk. This was thought to be helpful in cancer vaccines because the longer the vaccine sticks around in the body, the greater the immune response and the more T-cells that can be produced, Overwijk says.

But when mice were injected with an IFA vaccine against melanoma, the study reports that most of the T-cells in the bloodstream went to the site of the vaccine injection — not the tumor.

"The body doesn't know how to deal with the mineral oil [in IFA], and the body cannot get rid of that big blob of vaccine ... that sits under the skin. The T-cells go back and try to kill the oil, but they can't," he says.

When the oily IFA was replaced with water or saline — substances easily processed by mice and men — the T-cells migrated to the tumors and began to destroy them.

If these results hold up in humans, they could lead to a shift in the approach to making therapeutic cancer vaccines because most clinical trials now are testing vaccines that use peptides and IFA. "This finding applies to all of those — it's not limited to a certain cancer type," Overwijk says.

The results of this study confirm the findings of others in the field, and could be an important addition to cancer vaccine research, says Dr. Jeffery Weber, a tumor immunologist at the Moffitt Cancer Center in Tampa, Florida, who wasn't associated with the study.

"Though, one word of caution is that obviously the skin and the subcutaneous tissue of a mouse is a lot different than in a human, so it's a little hard to extrapolate. But within the reasonable limits I have some confidence," Weber told Shots.

Overwijk and collaborators at the University of Virginia expect to start a human clinical trial using saline or water-based cancer vaccines sometime this year. But, he says, these non-IFA vaccines have problems, too.

"While it is better than the IFA, we think water may actually be a little too ephemeral. Too short, and you don't get the activation of the immune system." Overwijk says. Another barrier is the difficulty in tracking human T-cells via biopsy — a process that wasn't necessary in mice, where the cells could be fluorescently labeled.

Though there are plenty of unresolved issue in cancer vaccine research, Overwijk says that these results could be important for improving future clinical trials. It's "an eye-opener," he says, a kind of "'Aha!' moment after years of using these same vaccines."

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Jessica Stoller-Conrad
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