Immunotherapy research helps remove 'invisible shield'
By Charlie Jolie
Doctors have been using immunotherapy to fight cancer since 1891, but the treatment suddenly is receiving a lot more attention. In August, former President Jimmy Carter said he is receiving immunotherapy as part of his treatment for melanoma, which Carter previously disclosed had spread to his brain. On Dec. 6, Carter announced that the most recent MRI scan of his brain didn't show any signs of cancer.
Even before Carter drew attention to them, immunotherapies were the hot topic of presentations and conversations at the American Society of Clinical Oncology’s annual meeting in June. Pharmaceutical companies now are advertising their brands of immunotherapies on television in hopes of driving cancer patients to seek the treatments from their doctors.
"These latest immunotherapy drugs, whether alone or in combination with other treatments, seem to be the future of cancer therapy," Carter, a patient at Emory University Hospital in Atlanta, said during a press conference in which he discussed his health. Furthering that perception, the U.S. Food and Drug Administration just declared two forms of immunotherapy “breakthrough therapies” — including the drug Carter is receiving, which has been the subject of a major study at Rush.
Getting past the ‘invisible shield’
The excitement around immunotherapy has been a long time in coming. For more than a century, researchers have been trying to understand why cancer seems to evade the human immune system, and they have developed treatments — immunotherapies — that use the body’s natural defenses to control some cancers.
Immunotherapies depart from the four main approaches to stopping cancer’s spread — surgical removal of a tumor, chemotherapy, radiation therapy and targeted therapies that interfere with cancer cell growth. While these treatments’ shared goal is killing the cancer cells themselves, immunotherapies are designed to help the human immune system better perform its primary task of identifying and eliminating potential threats.
Normally, human cells divide to form new cells as the body needs them, often after the immune system has identified and destroyed damaged or mutated cells. Then why, researchers asked, were cancer cells able to avoid detection and grow, or metastasize, without provoking an immune system response?
“An invisible shield on the surface of cancer cells inhibits specific proteins from sending a signal to the immune system that these cancer cells pose a threat and must be attacked,” says Philip Bonomi, MD, professor of medicine and director of the Division of Hematology, Oncology and Cell Therapy at Rush. Scientists only have come to identify and understand this shield and its workings in the past 20 years.
Releasing the brake
The immune system’s “seek and destroy” mission mostly is carried out by T cells — white blood cells that circulate through the body, scanning for cellular abnormalities and infections. They’re guided in their mission by what are known as checkpoint proteins, which are located on the surface of the healthy cells that the T cells scan. The checkpoint proteins signal that the cell is not a threat, leading the T cells not to attack them. Certain cancers seem to send out these same checkpoint proteins to the cell surface, tricking T-cells to not attacking them, either.
“Think of gas and brake pedals,” says Mary Jo Fidler, MD, an associate professor of medical oncology at Rush. “The presence of cancer cells should accelerate the activity of T cells, but the immune system checkpoints put on the brake signals instead. Checkpoint inhibitor drugs release these molecular brakes and thus augment the immune response.”
Developed in the last decade, checkpoint inhibitor drugs pembrolizumab (which Carter is receiving) and nivolumab are what are known as “monoclonal antibodies”: molecules engineered to mimic naturally produced proteins in the human immune system. In this case, the monoclonal antibodies attach to the deceptive checkpoint protein coming from the cancer cell to block its false "all clear" signal.
Rush has been part of clinical trials conducted over the past several years that indicate that lifting cancer cells’ shield allows T cells to recognize the cells as a threat and destroy them before they spread. In fact, Rush enrolled and treated one of the largest groups of patients who participated in a major study of the use of pembrolizumab to treat lung cancer. (Results of the study are pending.)
The U.S. Food and Drug Administration granted “Breakthrough Therapy Designation” to pembrolizumab last October and to nivolumab this September in an effort to allow more late stage cancer patients access to these drugs. The FDA confers Breakthrough Therapy Designation on drugs that “may demonstrate substantial improvement over existing therapies” for treating life-threatening conditions in order to speed the drugs’ development and review.
‘A paradigm shift in cancer’
Just in the last year, clinical trial results showing the effectiveness of checkpoint inhibitor drugs combined with more traditional methods of surgery, chemotherapy and radiation have added a sense of speed and enthusiasm not typically associated with the field of oncology. Jill O'Donnell-Tormey, chief executive officer of the nonprofit Cancer Research Institute, proclaimed 2015 "a truly special year for cancer immunotherapy” and “a paradigm shift in cancer, as more than half of the current cancer clinical trials include some form of immunotherapy."
The scope and pace of discovery has excited both doctors and patients, according to Bonomi. “The data shared at the American Society of Clinical Oncology annual meeting this summer is very exciting, because it shows longer survival times, lowered toxicity and the possibility that immunotherapies could treat more types of cancers,” he says.
“Despite high expectations, the results with a variety of immunotherapies had been relatively disappointing before the development of immune checkpoint inhibitors,” he adds. Utilizing antibodies to release the brakes on the immune system have resulted in improved survival for patients with advanced melanoma and widespread lung cancer and are showing promise in kidney cancer, mesothelioma, small cell lung cancer and in some colon cancers, Bonomi reports.
He also notes that other studies showed that side effects from checkpoint inhibitor therapies were measurably less than for chemotherapy. In addition, Bonomi says that the superior outcomes for melanoma patients when two different types of immune checkpoint inhibitors were combined “generated particular excitement, because there are many other novel immune stimulatory agents which can be incorporated into combination treatment regimens.”