Turning the immune system on cancer

A new type of drug can unleash immune system troops to fight cancers that have become impervious to chemotherapy. In several studies in the Nov. 27 Nature, scientists describe surprising results in patients using a novel approach that puts cancer cells on the radar screen of immune cells.

The new class of drugs aids the battle against cancer by neutralizing proteins that suppress the immune system response and allow cancer to escape surveillance.

“This is a whole new class of weapon” against cancer, says Roy Herbst, chief of medical oncology at Yale Cancer Center. The new drugs produced some stunning success stories in patients, but many people receiving them didn’t benefit in these studies. “We have to figure out if this is a paradigm that changes the way we look at cancer,” Herbst says. 

Cancer would seem easy for the immune system to detect. Cells replicating out of control display genetic mutations and rogue behavior. But tumors take advantage of a natural signaling process that balances two types of proteins against each other — some revving up an immune response and others suppressing it. Scientists call the slowdown signalers “checkpoints” because they prevent runaway immune reactions. Unfortunately, cancer is able to trip these immune checkpoints and escape surveillance.

By interfering with the checkpoint process, drugs in the new class restore some lost immune diligence.

For decades, cancer treatment has centered on radiation and chemotherapy. Recently some drugs that hit pivotal molecules in cancer have shown promise ( SN: 1/2/10, p. 15 ). But attempts to enlist the immune system using therapeutic cancer vaccines have been “underwhelming,” Herbst says. Targeting immune checkpoints is fundamentally different. While cancer vaccines are designed to trigger an immune response against cancer itself ( SN: 5/7/11, p. 20 ), the new class of drugs inhibits particular immune proteins to reawaken natural defenses that do the fighting.

In one of the new studies, 67 patients received a new drug called MPDL3280A, an antibody engineered to reverse an immune checkpoint signal. The patients had cancer of the bladder or nearby tissues that in most cases had spread to other organs. Chemo had largely failed these people. “They had effectively run out of options,” says Thomas Powles, a medical oncologist at the Barts Cancer Institute in London. The patients got intravenous injections every three weeks of MPDL3280A.

Two of the patients staged dramatic recoveries, and their cancer is now undetectable by X-rays. Sixteen patients showed substantial improvement, with tumors shrinking by at least 30 percent. The other patients’ tumors were stable or failed to respond to the drug.

In another study, Herbst and colleagues tested the same drug against lung cancer, melanoma, kidney cancer and other malignancies. These patients also had dwindling options before the study, but 32 of 175 showed substantial tumor shrinkage. A few seemed to vanquish their cancer entirely, he says.

In both studies, severe side effects were rare with MPDL3280A, which is made by the pharmaceutical company Roche of Basel, Switzerland. Genentech of South San Francisco, part of the Roche group, provided support for these two studies. Common problems were fatigue and low-grade fever. “I’ve been quite impressed,” Herbst says. “I’ve been giving patients chemo for 20 years. This is much better tolerated.”

The immune checkpoint that ratchets down the body’s defenses gets triggered when receptor proteins on the immune system’s T cells are tripped like a switch. The signal originates when a partner protein called a ligand from another immune cell binds to the receptor, fitting into it like a key in a lock. Earlier work showed that tumor cells can also release a ligand that latches onto a T cell receptor to mute immunity.

MPDL3280A neutralizes these ligands, short-circuiting the tone-it-down signal. This has the effect of waking up the T cell to go after tumor cells. MPDL3280A also thwarts the ligands produced by T cells themselves. The new research shows that patients who benefited the most from MPDL3280A had tumors that had attracted a lot of T cells. Before treatment, these immune soldiers were present but unable to respond, having gone into sleep mode.

“The army is standing there, a little stunned by the tumor,” says Jedd Wolchok, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City who was not involved in the studies. MPDL3280A stops the suppression signals.

“This jump-starts or catalyzes the system into action,” says Powles, and results in T cells attacking cancerous cells.

A third study in Nature finds evidence that specific T cells called CD8 cells carry the load in this fight. Researchers treated melanoma patients with pembrolizumab, one of the new drugs, and found that those who experienced tumor shrinkage were more apt to have ample CD8 T cells in or near their tumors than those who failed on the drug. CD8 T cells are immune shock troops. “When we released the brakes” by disabling the receptor with pembrolizumab, says UCLA physician Paul Tumeh, the CD8 T cells “just surged like crazy into the tumor.” Pembrolizumab is made by pharmaceutical giant Merck of Whitehouse Station, N.J., which helped support this study.

Pembrolizumab binds directly to the receptor, called PD-1. MPDL3280A neutralizes the ligand, preventing it from latching onto PD-1. Both sabotage the immune suppression signal. The Food and Drug Administration earlier this year granted both drugs special approval for use in certain patients.

PD-1 is one of several receptors that appear guilty of toning down immunity in cancer. Another receptor called CTLA4 was the first to draw fire. A drug called ipilimumab has been directed at it, with some success (SN:8/25/10, p. 12; 8/11/07, p. 88).

“We now have a group of drugs that targets cancer-related immune camouflage,” Powles says, “and this reactivates the immune system.” Finding additional receptors that tone down immunity would broaden the effectiveness of the strategy.

“This field is moving fast,” Herbst says.