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Immunotherapy: a New Weapon Against Cancer

Aug. 16, 2016

When Karen Koehler was diagnosed with chronic lymphocytic leukemia in 2011, she was told not to worry. She had a mild case that could simply be monitored, her doctor said. But two years later, the cancer took a turn for the worse when a genetic mutation made it aggressive and difficult to treat with chemotherapy. "I was told I had 10 months to live," says Koehler, 59, a retired teacher who lives in Park Ridge, New Jersey. At best, she was told, chemo might stretch that to two years.

Then Koehler was accepted into a clinical trial at Memorial Sloan Kettering Cancer Center in New York that aimed to turn her own immune cells into cancer killers. Within a month of treatment, her leukemia had vanished. "There were no cancer cells whatsoever," says Koehler, who remains cancer-free today.

The MSK oncologists whose research has helped Koehler are working on the latest entry in the booming arena of cancer immunotherapy. The potential of boosting the immune system's natural ability to fight off cancer was first realized with so-called checkpoint inhibitors, promising new drugs like Keytruda and Yervoy whose job is to block proteins that normally suppress immune function. These medicines are now being used to turn melanoma and lung cancer, once almost certainly terminal prognoses, into diseases that some patients can manage over the long term.



The newer therapy, dubbed CAR T for "chimeric antigen receptor T cell," is the next generation of immunotherapy: personalized one-time infusions of cells that destroy cancer and theoretically work in perpetuity to prevent it from coming back. In addition to the trials in blood cancers, these T cells "are being explored in ovarian, pancreatic, lung and brain cancer trials," says Dr. Jae Park, Koehler's oncologist at MSK. "There is definitely great potential here."

Working with biotechnology companies, doctors are creating the individually tailored treatments by removing T cells from patients' immune systems, engineering them to recognize and attack the patient's own particular cancer, expanding the population of the cells in a lab, then infusing them back into the body. The technology was designed to solve a fundamental problem: Because cancer involves a collection of normal cells growing out of control, the immune system doesn't recognize it as a foreign invader.

After Koehler's doctors harvested T cells from her blood in late 2014, the cells were altered to recognize a protein called CD19 that resides on the surface of blood cells that malfunction in chronic lymphocytic leukemia. These CAR Ts would thus be equipped to home in on the blood cells, known as B cells, and eliminate them. Koehler returned to Sloan Kettering in early 2015 to have the cells infused back into her body. Her doctors had warned that tests might show cancer for several months longer, though that didn't happen.

The first suggestion of the power of CAR Ts came from the University of Pennsylvania's Abramson Cancer Center, which is developing another CD19-targeted technology with the backing of the drug company Novartis. In early 2014, Novartis announced that 27 out of 30 patients with acute lymphoblastic leukemia who had not responded to traditional chemotherapy, most of them children, were in complete remission after having been treated. Novartis, Juno Therapeutics (the company working with MSK) and a third developer, Kite Pharma, predict that the Food and Drug Administration could approve their CAR Ts next year.

"The idea of reprogramming immune cells made sense to me," says Douglas Olson, 69, a retired medical device company executive from Bucks County, Pennsylvania, who received CAR Ts in a Penn trial in 2010 after his leukemia returned. He gets regular checkups and blood tests several times a year, all of which have been clean since three weeks after his treatment. Olson has even taken up running since his cancer battle and has finished five half marathons. Eight of the 14 patients in the trial Olson participated in responded to the engineered cells. One of the questions researchers at Penn, MSK and other cancer centers hope to answer is why the engineered cells work for some patients but are ineffective in others.



Since the treatment affects some normal immune cells as well as the cancer cells, Olson, Koehler and other recipients may need infusions periodically to restore normal immune cells to their bloodstreams. That's a manageable effect of treatment. For some patients, the one potentially serious effect is what's called "cytokine release syndrome," a dangerous overwhelming immune response that occurs shortly after the treatment when CAR T cells encounter cancer cells and begin working.

The disorder can cause high fevers and dangerous drops in blood pressure and kidney function, putting some patients in intensive care.

Neurological symptoms like confusion and seizures are also a risk. Steroids can be helpful in managing some of the symptoms, and an immune-suppressing drug called tocilizumab, usually used to treat rheumatoid arthritis, has been shown to be effective in controlling these short-term problems.

"We're working on trying to prevent" side effects, says Dr. William Wierda, a professor in the department of leukemia at Houston's MD Anderson Cancer Center, which is participating in several CAR T clinical trials. "In some cases, we can identify patients who are at higher risk of cytokine release syndrome. And now we're discussing whether tocilizumab could be used to prevent it."

Researchers are also developing CAR Ts that will work against other cancers, including tough-to-conquer solid tumors like ovarian and pancreatic cancers and glioblastoma, the aggressive brain cancer. The biggest challenge in fighting solid tumors is finding targets like the CD19 protein. "Solid tumors have unique ways of avoiding the immune system that blood cancers do not," says Dr. David Porter, a physician and director of blood and bone marrow transplantation at Penn's Abramson Cancer Center. "One issue is that solid tumors are all wrapped up in a mass, making it difficult for T cells to be able to get in and kill the cancer cells." Penn scientists are examining one potential target on glioblastoma tumors called EGFRvIII. About 30 percent of patients have tumors that produce this protein, and trials are now starting of CAR Ts that have been engineered to attack those tumors.

The process of using CAR Ts to treat cancer will not only extend to many more tumor types, it will also become more streamlined and easier for patients, predicts Sloan Kettering's Park. He believes the T-cell collection process will eventually "be like getting a blood draw from your doctor's office." The engineering time will be shortened and perhaps even automated, he says. "It only gets better from here."

http://health.usnews.com/health-news/patient-advice/articles/2016-08-16/immunotherapy-a-new-weapon-against-cancer