New cancer therapy liberates captive cancer-fighting T-cells

Imagine the A-Team without Mr. T.

Unthinkable.

How could the team's plan come together without their muscle man, with his imposing mohawk, gold chains and sleeveless vests?

Yet that's the fate of the human body trying to fight cancer, when its T-cells � the muscle men of the immune system � are turned off.

Like a villain from the hit 1980s TV series, who might try to kidnap Mr. T to prevent him from rescuing his friends, cancer paralyzes the body's defenses, allowing tumors to grow and spread unopposed.

Cancer ties up T-cells in a clever way � by hijacking the body's natural system for regulating itself. That's why scientists are trying to be just as clever, creating drugs that work in new ways to harness the immune system's power. At this weekend's meeting of the American Society of Clinical Oncology in Chicago � the scientific community's annual showcase for the latest advances against cancer � researchers presented several new strategies to liberate captive T-cells.

"It's a different kind of cancer therapy," says oncologist Suzanne Topalian, who was involved in studies of two new drugs and will present her research today. "It doesn't kill cancer cells directly. It acts through the immune system. We're enhancing a response that's already there, but at an ineffective or weak level."

None of these new drugs cures cancer.

And, so far, they've been tested only in the very earliest of human trials, says Topalian, a professor of surgery and oncology at the Johns Hopkins University School of Medicine in Baltimore.

But Topalian says she's excited that two of the drugs she's studied show promise not just in melanoma and kidney cancer, which have long be susceptible to immune therapies, but also in lung cancer, in which immune therapy has never worked well.

These two new drugs also controlled cancer better than most drugs at this early stage of testing, when failure is the norm, says James Gulley, an immune therapy researcher at the National Cancer Institute.

In a study of 296 patients with advanced tumors, a drug called an anti-PD-1 antibody shrank tumors by at least 30% in 18% of lung cancer patients; 28% of melanoma patients; and 27% of kidney cancer patients, according to a paper published today in the New England Journal of Medicine.

In a second study of 207 patients with advanced disease, a drug called an anti-PD-L1 antibody shrank tumors in 10% of lung cancers; 17% of melanomas; 12% of kidney cancers; and 6% of ovarian cancers, according to the paper, also published in the New England Journal of Medicine.

While doctors would prefer to cure patients, shrinking their tumors can make people feel a lot better, Gulley says.

Shrinking tumors can give people more energy, because the cancer is sapping less of their strength. It can also relieve pain, if a tumor was pressing on a nerve, Gulley says.

And while many cancer drugs keep tumors under control for just a few months, Gulley notes that many patients in this study benefited for a year or more. If patients are doing well, Topalian says, patients can be treated for two years.

Both drugs work in novel ways.

Normally, when the body faces an immune threat, it activates lots of T-cells to kill the intruders, Topalian says.

But just as the A-Team doesn't want Mr. T to go berserk, the body also needs to keep T-cells under control.

So each T-cell also has a shut-off switch, in the form of a receptor on its surface, called PD-1, or programmed death-1. Without a way to turn the T-cells off, and even kill many of them, they could turn their destructive power on the body and damage it, Gulley says.

In some ways, the PD-1 shut-off receptor is like a lock, Topalian says. Unfortunately, many cancer cells have the key, called PD-L1.

The first study presented at ASCO tests a drug to block that receptor, called an anti-PD-1 antibody, which acts as if it's jamming the lock, so cancer cells can't open them. That leaves T-cells free to continue killing.

The second study tested a drug called an anti-PD-L1 antibody, which keeps cancer cells from using their shut-off keys. That also allows T-cells to continue killing.

But revving up the immune system has a price: 14% of patients in the first study and 9% of those in the second study had severe or life-threatening side effects, according to the studies. Three patients in the first study died from lung problems.

Doctors consider those risks acceptable, however, given that patients in the study had incurable cancers that would almost certainly prove fatal, Gulley says.

Topalian says her study provides clues about ways to reduce those risks.

Researchers also developed a test for sensitivity to the drug. None of those with negative results responded to the anti-PD-1 antibody. However, 36% of those with positive results did, Topalian says.

If those test results are confirmed in larger studies, that suggests that doctors could use them to tailor treatments, giving the new immune therapies only to patients most likely to benefit from them, Topalian says. Patients unlikely to benefit could skip the drug � and the side effects.