'Checkpoint inhibitors' show promise in cancer fight

Oncologist-immunologist Robert Vonderheide of the University of Pennsylvania's Abramson Cancer Center is studying immunotherapy approaches to treat pancreatic cancer.
Oncologist-immunologist Robert Vonderheide of the University of Pennsylvania's Abramson Cancer Center is studying immunotherapy approaches to treat pancreatic cancer. (Penn Medicine)
Posted: June 09, 2014

In 2010, metastatic melanoma roared into Julius Rauch's lungs and spine, no longer tamable using conventional treatments.

With maybe four months left to live, Rauch got into a clinical trial of an experimental drug.

Today, the 76-year-old retired real estate developer enjoys fishing, golfing - and a remission that has lasted nearly four years. The drug, Bristol-Myers Squibb's Yervoy, or ipilumimab, was approved in 2011, the year after it eradicated his cancer. It became the first in a new class of immune-stimulating drugs called checkpoint inhibitors, and only the second immunotherapy on the market.

Here's the best part: Yervoy was just the beginning. At least seven companies are now testing their own checkpoint inhibitors in cancers of the lung, kidney, colon, brain, and other organs, as well as melanoma. Three big companies - Bristol-Myers Squibb, Roche, and Merck - are racing toward U.S. Food and Drug Administration approval of their versions, perhaps by the end of next year.

And though Rauch calls his resurrection "a medical miracle for sure," it was no fluke.

"We've all had those kind of stories with different tumor types," said oncologist Julie Brahmer at the Johns Hopkins Kimmel Cancer Center in Baltimore, where she is testing a checkpoint inhibitor in lung cancer patients.

This new class is stirring excitement not only because of such remissions, but because of the novel way it works, removing an immune system brake or checkpoint that cancer exploits.

Immunotherapy - activating the body's immune cells to kill its renegade cells - has been the holy grail of oncology for more than a century. Now, cutting the brakes and several other activation strategies are proving so successful that immunotherapy updates were highlights of last week's annual meeting of the American Society of Clinical Oncology, the 30,000-member organization of cancer specialists.

"We are going to look back at this time and recognize it as a turning point for immunotherapy," said Robert Vonderheide, an oncologist-immunologist at the University of Pennsylvania's Abramson Cancer Center, where Rauch got Yervoy.

Conventional chemotherapy remains the backbone of oncology. Alas, these cell-killing drugs are not selective - they poison fast-dividing cells, healthy as well as malignant - and cancer often mutates to overcome the toxic effects.

More-selective drugs have revolutionized treatment over the last two decades. "Targeted" therapies, such as Herceptin and Gleevec, work by disrupting a specific molecule that plays a vital role in cancer growth and survival. Still, cancer can find ways to morph and defy even these sophisticated weapons.

One of the most tantalizing prospects of immunotherapy is longer-lasting cancer control. Activated immune cells retain a permanent memory of the cancer cells' unique protein marker, or antigen. If cancer reappears, the immune cells reactivate.

"Immunotherapy works on the immune system, not a pathway within the cancer. There is some evidence that it can develop immune memory, so the remissions are more durable," said Elizabeth Plimack, a genitourinary oncologist at Fox Chase Cancer Center, who is helping to test checkpoint inhibitors in kidney and bladder cancer patients.

That's not to suggest immunotherapy will become a cancer cure-all.

Although the immune system is programmed to kill invaders such as bacteria and viruses, inducing it to attack its own body's abnormal tissue is complex and risky. The side effects can be autoimmune damage - or complete self-destruction. "The toxicities do tend to run higher. We did see some liver damage, but, fortunately, it was reversible," Plimack said of patients testing Bristol-Myers' checkpoint inhibitor nivolumab.

Nor can researchers predict which patients will respond to the costly therapies, at least not yet. Though Yervoy (more than $100,000 for a course) was stunningly effective for Rauch, it didn't help T.J. Sharpe, philly.com's Patient #1, who has been blogging about his nearly two-year battle with metastatic melanoma.

Then again, Merck's checkpoint inhibitor, pembrolizumab, has so far shrunk Sharpe's tumors by 70 percent. He has gotten intravenous doses for about a year in a trial.

"I can do things again. I went running this morning. I went camping with my kids," said Sharpe, 39, a South Jersey native who now lives in Fort Lauderdale, Fla. "This treatment has given us back some of the future we had always taken for granted."

Only one other approved immunotherapy is on the market: Dendreon Corp.'s Provenge for prostate cancer. A so-called cancer vaccine, it is made by removing certain immune soldier cells from the patient's blood and engineering them to carry an antigen found on most prostate cancer cells. When the soldiers are returned to the patient, they signal T cells, the big guns of the immune system, to attack anything bearing the telltale antigen.

An even higher-tech approach - in which the patients' T cells are genetically engineered to make them attack certain blood cancers - has succeeded in trials at Penn, Children's Hospital of Philadelphia, and a growing number of centers. (Big Pharma is investing in this; witness Penn's partnership with Novartis.)

Checkpoint inhibitors offer a simpler - not to say simple - way to rev up T cells: cut one of the brakes that holds them in check. The immune system has numerous molecular brakes, or checkpoints, designed to prevent or abort attacks that could be self-destructive.

Yervoy cuts a brake known as CTLA-4; the inhibitors still in clinical trials remove brakes known as PD-1 and PD-L1.

"Every time our immune system is stimulated, there are brakes. Otherwise, everyone would get autoimmune diseases like lupus and arthritis," said Penn oncologist Lynn Schuchter, who is testing several checkpoint inhibitors.

Editor's Note: This story was updated to correct the name of Merck's checkpoint inhibitor. It is pembrolizumab.


mmccullough@phillynews.com

215-854-2720 215-854-2720

@repopter

Call using Skype Send SMS Learn more You'll need Skype CreditNo Skype credit required

comments powered by Disqus
|
|
|
|
|