Cancer Immunotherapiest Emerge as Game Changers: Institute researchers always believed the immune system could be coaxed to fight cancer. They were right.

July 13, 2015

"It’s a miracle drug, and I thank my lucky stars I’ve cheated death." — Hans Christensen

After Hans Christensen had a melanoma mole removed from his lower back 18 years ago, his doctors told him there was little chance of recurrence. So 11 years later, when he got a bump near the original excision, he didn’t think anything of it.

It was the summer of 2007, and the 50-year-old electrician was visiting his family in Denmark when he started having trouble breathing. Tests revealed the cancer had come back with a vengeance, spreading to his lungs and intestines and consuming so much of the bone in his left humerus that surgeons thought they would have to amputate.

Surgery and chemo beat back the melanoma. But it was only a temporary reprieve, and Hans’ prognosis was poor—until he entered a clinical trial in Los Angeles in 2008 that was testing an experimental drug called ipilimumab (Yervoy), which boosts the immune system response to cancer.

Two years after starting infusions of the therapy, he finally got good news: there was no evidence of cancer. “It’s a miracle drug, and I thank my lucky stars,” says the resident of Newhall, California. “I’ve cheated death.”

Ipilimumab is just one of a new generation of cancer therapies that are revolutionizing the treatment of this dreaded disease. These drugs are significantly different from conventional cancer treatments, which include chemotherapy, radiation and newer medications that target genetic mutations in tumors that spur unchecked cell growth. Instead of attacking the tumors themselves with the aim of killing them, immunotherapies rally the body’s natural defenses and unleash the immune system to vanquish the cancer.

"Up until now, treatments for advanced cancers were merely ways of buying time for patients and extending survival, but these new therapies are game changers because they have the potential of fixing a cancer in a more long-term way." — Dr. Mark B. Faries

Signaling a flurry of progress, the Food and Drug Administration (FDA) in the past year has green-lighted two immunotherapies to treat patients with advanced melanoma: pembrolizumab (Keytruda) and nivolumab (Opdivo). The FDA also gave the go-ahead for using nivolumab in metastatic lung cancers.

These medications, which are given by infusion, are now being tested against a host of other types of cancers, including bladder, kidney, head and neck, breast, Hodgkin’s lymphoma and multiple myeloma. More drugs are in the testing pipeline.

“Up until now, treatments for advanced cancers were merely ways of buying time for patients and extending survival,” says Mark B. Faries, MD, director of the Donald L. Morton, MD, Melanoma Research Program and director of therapeutic immunology. “But these new therapies are game changers because they have the potential of fixing a cancer in a more long-term way.”

The idea of boosting a patient’s own immune system to fend off cancer is not a new one. In 1891 William Coley, MD, a pioneering cancer researcher in New York City, observed that in patients with inoperable cancer, an injection of certain types of bacteria shrank tumors—especially in patients who had a fever or signs of an infection, which would indicate they were mounting an immune response.

Institute co-founder Donald L. Morton, MD, was an early advocate of finding ways to harness the immune system’s power to fight cancer. In the early 1970s, he pioneered a method of injecting Bacilli Calmette-Guérin (BCG), a weakened strain of the tuberculosis bacterium, directly into melanoma tumors, which was the first successful use of immunotherapy against metastatic human cancer.

But many obstacles remained. For a while, there was a lot of interest in therapeutic anti-cancer vaccines. But nothing seemed to work, or the therapies worked only in rare cases or for just a few types of cancers. In general, cancer cells were able to slip through the body’s defenses and evade the immune system, which has built-in mechanisms that stop it from attacking other normal cells in the body.

There are several molecules on the surface of immune cells that need to be activated to launch an immune response. But because cancer cells share traits with healthy cells, the immune system doesn’t recognize them as aberrant, and cancer cells avoid detection. The new drugs help the body circumvent this bit of subterfuge.

“They’re known as checkpoint inhibitors because they block tumor growth at multiple points along the biological pathways,” says Omid Hamid, MD, chief of translational research and immunotherapy at The Angeles Clinic and Research Institute and an Institute adjunct faculty member.

In 2011 the first of these drugs gained FDA approval. Ipilim¬umab is now used for metastatic melanoma. The drug is the first melanoma treatment that actually extended survival for people with late-stage disease. More than 20% of the patients were still alive three years later; most of them would have died otherwise.

The drug thwarts the action of a protein known as CTLA-4.

This is a checkpoint molecule that acts as an “off switch” that cripples the T cells—the immune system’s foot soldiers—and stops them from harming healthy cells. But it can also block the T cells from attacking tumors.

Meanwhile, pembrolizumab and nivolumab target other proteins on the surface of cells—called PD-1 and PD-L1—that also act as immune system brakes. Pembrolizumab produces a response in a stunning one-third of patients.

"Bolstering the immune system response seems to be giving us the ability to generate a more durable long-term response” in people with cancer that was once viewed as terminal, Dr. Hamid says. “There’s more to come, It’s really an amazing time.”

The checkpoint inhibitors represent only one new immunotherapy approach. Scientists are studying tumor-infiltrating lymphocytes (TILs), which are cells produced to repel foreign invaders. Scientists can remove these cells from tissue samples taken from patients and then multiply them in the lab by treating them with interleukin-2. Then they are injected back into the patient.

This strategy has been deployed successfully to treat melanoma patients at major research institutions like the National Institutes of Health. Now researchers at the John Wayne Cancer Institute are hoping to move ahead with clinical trials using this approach. Their laboratories have been certified by the FDA, and they’ve removed tumor cells from five patients in preparation for human tests.

“Because the therapy is so complex and difficult to do, no place outside of some massive research institution could conceive of experimenting on it,” Dr. Faries says. “But we’re trying to show that this type of therapy can be done at a place like the John Wayne Cancer Institute, which would open the door to more widespread use of this approach.”

Institute researchers are also taking a closer look at BCG and how it works in fighting cancer. The hope is to uncover other immune system pathways that could potentially be enlisted to attack tumor cells.

At the Institute, patients with advanced melanomas on their skin are still treated with BCG, which can have a remarkable effect. (Almost 600 patients have undergone BCG therapy at the Institute.) Injections of the bacteria into the cancerous lesions underneath the skin can eradicate dozens of small tumors.

“We get patients with many bumps in the area of the tumor, and we can’t cut them all out,” says Delphine J. Lee, MD, PhD, director of translational immunology and director of the Dirks/Dougherty Laboratory for Cancer Research. “We’ve observed that in some patients over several months, the injections of BCG will just melt them away including the bumps that weren’t injected.”

That’s the immune system at work. Now Dr. Lee and her colleagues are trying to decipher precisely what BCG does to stimulate this immune response. Dr. Lee likens immune cells to the police that go on patrol looking for miscreants, but not all of them do their job.

“Some ‘police’ look the other way, or they’re asleep or they don’t even bother,” says Dr. Lee. “These ‘lazy’ immune cells [bad macrophages] infiltrate inside the tumors.” But in laboratory experiments with human tumor cells in a test tube, researchers found that BCG somehow awakens these macrophages and gets them to function better.

“The fact that BCG can change the behavior of these bad macrophages and transform them into good ones points out how important these microbes may be,” she says. “Understanding how they work could open up a whole new immunotherapy approach to treating cancer.”

To learn more about supporting research on immunotherapies, please call Michael Avila in the Development office at 310-829-8361 or michael.avila@ stjohns.org.

USING THE IMMUNE SYSTEM TO ASSESS CANCER PROGNOSIS

For decades, doctors used the size of tumors to determine cancer severity, treatment options and prognosis. But tumor size—or staging—is an imperfect diagnostic measurement.

Now Institute scientists are trying to devise a better tool for predicting survival in breast cancer using information from a patient’s immune system that is contained in the tumor infiltrating lymphocytes (TILs). They correlate each patient’s tumor biology with how well the patient did. To do this, they’re using an immunoscore based on five immune variables that was developed, initially for colon cancer, by a research team led by Anton J. Bilchik, MD, PhD, professor of surgery, chief of medicine and chief of the gastrointestinal research program.

“Every patient behaves differently,” says Rashmi Bawa, MD, the John Wayne Cancer Institute Auxiliary breast fellow. “We’re trying to determine how well patients will respond to treatment and their overall survival. Hopefully this approach will give us some answers, help patients and fill a huge gap in our knowledge base.”