Conquering Cancer by Thwarting Tumor's Immune Shield

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Jocelyn Kaiser
2012-06-02 (All day)
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A type of drug that helps the body's immune system attack tumors is showing promise. In early clinical trials involving several hundred patients with various kinds of advanced cancer, up to one-quarter of those who received the treatment saw their tumors shrink, and some are still alive more than a year later.

The results are the latest good news for so-called immunotherapy treatments that work by overcoming a tumor's ability to evade the immune system. One way cancer cells escape destruction is by producing a protein on their surface, known as programmed death ligand-1 (PD-L1), that locks onto a protein called PD-1 on T cells, a type of immune cell. When the two connect, that prevents T cells from detecting the tumor and signaling the immune system to attack. Researchers have hypothesized that giving people with tumors an antibody (a protein) that blocks either PD-1 or PD-L1 would keep the proteins from engaging and switching off T cells—and a small initial clinical trial of an anti-PD-1 drug confirmed that this strategy holds promise for treating cancer.

So do two larger, multicenter studies of this approach, which are being presented today at the annual meeting of the American Society of Clinical Oncology in Chicago. When a group of 296 patients with five types of advanced cancer received an infusion of an antibody targeting PD-1 every 2 weeks, tumors shrank in 14 of 76 lung cancer patients, 26 of 94 melanoma patients, and 9 of 33 kidney cancer patients—an 18% to 28% response rate. Many patients have responded to the drug for a year or longer. "These are very encouraging signals," says melanoma researcher Suzanne Topalian of Johns Hopkins University in Baltimore, Maryland, a leader of the multicenter study.

In a separate study at Hopkins and elsewhere in which 207 cancer patients received an antibody that blocks PD-L1, 10% to 17% of those with one of three types of cancer have responded, and some patients have responded for at least a year.

As with most early drug studies, the trials were predominantly designed to test safety; more studies are needed to show whether those receiving the antibodies live longer than they would on conventional treatments. (Topalian says the 1-year survival results are encouraging, however. In other studies, advanced melanoma patients on standard treatment lived for 6 to 7 months on average.) And the drugs, both made by Bristol-Myers Squibb, can result in severe side effects: The anti-PD-1 drug caused three deaths from lung inflammation.

Still, the fact that both drugs seem to have a clinical impact "says that this combined [PD-1/PD-L1] pathway is important as a target for cancer therapy," Topalian says. When researchers tested tumor samples from 42 of the patients receiving anti-PD-1, nine of 25 who responded had PD-L1 on their tumors, while none of those lacking PD-L1 on their cancer cells responded. That means a test for PD-L1 could potentially tell doctors which patients should get the drug, much as physicians now routinely test breast cancers to see if they should receive various hormone therapies.

The two trials, whose results are also reported online today in The New England Journal of Medicine, have "broken the ceiling" of a 10% to 15% response rate for a similar strategy that targets a T-cell protein called CTLA-4, says oncologist Antoni Ribas of the University of California, Los Angeles, who wrote an accompanying commentary in the journal. A CTLA-4-blocking antibody called ipilimumab was approved for melanoma treatment by U.S. regulators last year. But it seems to cause more side effects than anti-PD-1 drugs, probably because CTLA-4 is present on T cells in more tissues of the body.

"The biggest feature of all these approaches is that it engages [an immune] memory response, so responses tend to be durable," says Ribas. Still, one significant remaining challenge is to get more patients to respond to the growing number of these immunotherapy drugs. One way to do that may be to combine them with other treatments, Topalian says.

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