A vaccine that thwarts cancer cells has so far proved to be better in theory than in practice, and researchers may finally understand why.
The possibility of turning the body’s own immune system against tumor cells has hovered like a medical mirage over the cancer-research community for decades. While tumors emerge from healthy cells that start to grow with abandon, they have enough tumor-specific features that should make them easy targets for an alert immune system that’s trained to distinguish between molecular friends and foes. And this idea was supported by several encouraging trials of therapeutic cancer vaccines, which effectively shrank tumors in cell cultures in the lab.
But when these promising vaccine candidates, including ones against melanoma and lymphoma, were tested in patients, they invariably disappointed. While they promoted some immune response from the cancer patients, this response wasn’t enough to make a dent in tumors. Now researchers report in the journal Nature Medicine that the vaccines themselves may be at fault.
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Willem Overwijk, an associate professor in the department of melanoma medical oncology at MD Anderson Cancer Center, and his colleagues found that a mineral oil known as incomplete Freund’s adjuvant, or IFA, that is added to cancer vaccines to stimulate the immune system, may do too good a job. IFA effectively activates the body to produce T cells, which are supposed to then target cancer cells and destroy them, shrinking tumors and preventing them from spreading to other locations and seeding new growths. But because the IFA is not biodegradable, it remains under skin at the injection site, acting as an irresistible lure for the T cells.
In studies with mice that were injected with a promising vaccine against melanoma, Overwijk was able to document that instead of zeroing in on the tumor, the T cells started to attack the IFA instead. “While the vaccine successfully activates T cells, those T cells then circle back to the injection site where the mineral oil is still sitting under the skin,” says Overwijk. “Very few T cells make it to the tumor; they prefer to go back to the vaccination site.”
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Essentially, he says, the vaccine is competing with the tumor for the attention of the immune cells, and 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,” says Overwijk.
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 the oil, known as an adjuvant, is part of the problem, then switching to a less potent one may improve responses to cancer vaccines. That was the case when Overwijk and his colleagues tested the same vaccine that was made with a water-based adjuvant instead of IFA; the trade-off, of course, is that the vaccine may not awaken the immune system as effectively as IFA, but the weaker response may be compensated by a stronger T-cell response against the tumor itself.
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So why is IFA used in vaccines if it works against the immunization? It’s very effective in shots designed to generate antibodies against bacteria and viruses, so researchers assumed that it would also be a potent ally in the fight against tumor cells. When that didn’t turn out to be the case, scientists still stuck with the oil, looking instead to other factors like the tumor’s ability to thwart the immune system, to explain why the vaccines weren’t so effective in shrinking tumors in patients. “The adjuvant was the last place we thought to look,” says Overwijk.
But it’s now possible to generate strong immune reaction without IFA, using molecules that weren’t available until recently. Already, researchers at MD Anderson are collaborating with scientists at the University of Virginia to test a melanoma vaccine that will be made in two formulations — one with IFA and another with an immunostimulatory molecule. The team will be taking biopsies of the immunization site and measuring levels of T cells generated by the shot; hopefully the vaccine without the IFA will show fewer T cells congregated around the shot site, which would mean more of these had found their tumor targets.