New method of cancer immunotherapy developed

Carolyn Bertozzi, a professor of chemistry at Stanford University, has shown that removing certain sugars surrounding breast cancer cells can recruit a second arm of the immune system - the innate immune system.

The approach, described in a study published this week in Proceedings of the (U.S.) National Academy of Sciences, greatly improved the effectiveness of a breast cancer drug in a lab dish, opening up a new avenue in the fight against cancer.

"This is a whole new dimension to immune therapy," Bertozzi said, adding that she thinks it could be the first of many therapeutic approaches involving the sugars that surround cells, called the glycocalyx. "People in this field are starting to appreciate that there are many different nodes that you need to affect to get a more robust immune reaction against a tumor, and the glycocalyx appears to be one of those nodes."

Researchers have long known that if certain sugars are present on a tumor, it is less likely to respond well to therapies, according to a news release from Stanford. But nobody knew what that halo of sugars was doing, in part because such a small number of labs study the glycocalyx.

Evidence had been mounting within those few labs that do study the glycocalyx, including Bertozzi's, that a subset of sugars called sialic acids act as a signal for the innate immune system to ignore the otherwise suspicious-looking tumor. Eliminate those sugars, and maybe innate immune cells would be more likely to recognize and attack the cancer cells, Bertozzi thought.

Bertozzi and her team worked with breast cancer cells in the lab that had varying amounts of a protein called HER2 on the surface. Women whose tumors have that protein at high levels generally receive a therapy called Herceptin, which is an antibody that binds to HER2 and flags the tumor cell for destruction by innate immune cells, such as natural killer (NK) cells and macrophages.

But Herceptin does not always work, especially in tumors with less abundant HER2, and if sialic acids are present on the cancer cell surface, then it is even less likely to be effective.

The Stanford team used chemistry tools they had created in previous work to attach what is essentially a chemical lawn mower onto the Herceptin antibody. Once the drug bound to HER2 molecules on the cancer cell, the chemical mower sliced off the neighboring sialic acids.

With those sugars gone, Herceptin became significantly more likely to activate NK cells to kill the cancerous cells, especially in cases where the cells had lower levels of HER2 and higher levels of sugars. This all took place in a lab dish, but Bertozzi is hopeful a version of this strategy could be effective in people.

"All of the world of immune therapy is now thinking about the immune system as calculating pluses and minuses. If you want to tilt the scale toward immune activation, you can either augment the activator or remove inhibitor, or both," said Bertozzi. Endit