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Self-sabotage

Conquest - Summer 2013

Why cancer vaccines haven't worked

By Joey Tran and Scott Merville

Willem Overwijk

Willem Overwijk, Ph.D., associate
professor, Department of
Melanoma Medical Oncology
Photo: Wyatt McSpadden

A vaccine that launches an immune attack on cancer cells has so far proved to be better in theory than in practice, and researchers may finally understand why.

Willem Overwijk, Ph.D., associate professor in MD Anderson’s Department of Melanoma Medical Oncology, and his colleagues found that a mineral oil known as incomplete Freund’s adjuvant (IFA), added to cancer vaccines to stimulate the immune system, might do too good a job.

The vaccine effectively activates T cells, which are supposed to target cancer cells and destroy them — shrinking tumors and preventing them from spreading to other locations and seeding new growths. But because IFA is not biodegradable, it remains under the skin at the injection site, acting as an irresistible bait for the T cells.

“Vaccines stimulate production of T cells primed to attack the target cancer, and there are many T cells in the bloodstream after vaccination. We found that only a few get to the tumor while many more are stuck at, or double back to, the vaccination site,” Overwijk says.

Essentially, he says, the vaccine competes with the tumor for the attention of the immune cells. The vaccine, because of its powerful ability to stimulate the defensive cells, tends to be more dominant. “That explains why we find nice levels of T cells in blood after vaccination but no correlation with a response against tumors in patients,” Overwijk says.

Engineering flaw discovered 

The oil may not be the only saboteur. It’s also possible that the tumor itself sends out inhibitory factors that either disguise the tumor from immune sentries, or discourage T cells from venturing too close. But if oil is part of the problem, then switching to a less persistent formulation may improve responses to cancer vaccines.

Meanwhile, Overwijk and his colleagues infer that a possible solution would be to reduce the size and persistence of vaccine “depots” at the injection site. They’ve tested a vaccine based on a biodegradable saline solution instead of IFA, and found antigens cleared more quickly but did not spark the desired T cell response. Adding co-stimulating agents to the saline vaccine corrected this effect, allowing more T cells to attack the tumor and leaving few at the injection site.

“It’s an engineering flaw in those vaccines that we didn’t appreciate until now,” Overwijk says. “Fortunately, our results also directly instruct us how to design new, more powerful vaccine formulas for treating people with cancer.”

Reported in the March 3, 2013, online edition of Nature Medicine

See MD Anderson’s online Newsroom and Cancer Frontline for more information on these and other basic, translational and clinical research findings at MD Anderson.

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