Immune Boost

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In the long search for tools to fight cancer, researchers have hit upon a brilliant strategy: harness the body’s own immune system, which fights illnesses like the common cold, to beat back cancer cells.

Immunotherapy has been used to treat other diseases, including viral diseases such as the common cytomegalovirus, which can cause mononucleosis and hepatitis, and HIV. Cancer vaccines, which have been used to treat prostate and bladder cancers, are a type of immunotherapy, as are stem cell and bone marrow transplants, which support the immune system after cancer treatment. But scientists have only recently developed treatments that work by stimulating a patient’s immune system to recognize and target cancer cells.

Over the past few years, this cell immunotherapy, which makes use of a patient’s own T cells—a type of white blood cell essential to the immune system—has moved into clinical trials at several cancer centers, including here in Seattle. The trials are generally small, but many have yielded impressive results. For example, recently, doctors used T cell immunotherapy in a clinical trial at Seattle Children’s Research Institute (SCRI) to treat acute lymphocytic leukemia (ALL), and 93 percent of children enrolled in the trial achieved complete remission.

Chemotherapy can cure about 80 percent of patients with ALL, but the remaining 20 percent are left with few other treatment options. “Many of these patients have had failed bone marrow transplants or have a disease that relapsed or didn’t respond to chemotherapy, so all that was left was hospice care,” says Dr. Mike Jensen, director of the Ben Towne Center for Childhood Cancer Research at SCRI, who led the research team. “It’s been extraordinarily exciting to see this trial play out.” A cure for this blood and bone marrow cancer would be particularly significant because ALL is the most common form of cancer in children.

To create this treatment, T cells are collected from a patient’s blood and reengineered in a lab so that the cells can recognize and target cancer cells. “We can make a T cell do something it couldn’t naturally do, which is to have a sort of Velcro lock on a cancer cell and turn on the machinery to kill that cell,” says Jensen, a pioneer in this type of immunotherapy. The “Velcro” receptors, called chimeric antigen receptors (CARs), are proteins that allow the T cells to recognize another specific protein on tumor cells. The reprogrammed cells are then infused into the patient, and can hunt down and destroy cancer cells. Some patients undergo chemotherapy before the infusion of CAR T cells to give these reengineered cells the best possible chance of killing the cancer.

The SCRI trial is only one of many recent cancer immunotherapy trials in which doctors have achieved remarkable results in patients for whom surgery, radiation and chemotherapy were not effective. (Cell immunotherapy is still being tested in experimental trials that are run out of research labs, so patients must be enrolled in those trials in order to receive the treatments.)

Seattle has been one hub for this research. Researchers at the Fred Hutchinson Cancer Research Center have been working on other studies, with CAR T cell immunotherapy clinical trials underway for small-cell lung cancer, malignant melanoma and acute leukemia; and further clinical trials for treating ovarian and pancreatic cancers are likely to move forward this year. Last November, the cancer center opened the more than 9,000-square-foot Bezos Family Immunotherapy Clinic. The clinic is set to double the number of clinical immunotherapy trials at Fred Hutch this year.

Amazon founder and CEO Jeff Bezos tours the new Bezos Family Immunotherapy Clinic at the Fred Hutchinson Cancer Research Center, which will significantly increase the number of trials that the Hutch can conduct

But while saving kids—and adults—from dying of cancer sounds like the best thing to happen to cancer research in decades, immunotherapy is still more promise than panacea in many instances. Many patients in T cell therapy trials are not responding to the therapy, and researchers are challenged in using immunotherapy to battle some common cancers. For example, solid tumors, such as in breast, prostate and colon cancers, are proving harder to treat. “They pose some additional obstacles,” says Dr. Philip Greenberg, a founding member of the Fred Hutch and University of Washington immunology programs, whose Fred Hutch lab is currently conducting several cell immunotherapy trials. “They tend to create an environment around themselves that makes them much more difficult for the immune system to efficiently target and eliminate.”

Another issue is the treatment side effects that have shown up in the CAR T trials that were successful in getting patients into remission. A small number of these patients have experienced highly toxic side effects when a hyperstimulated immune system attacks their healthy organs.

“There have been red flags,” says Luke Timmerman, editor of the Timmerman Report, a Seattle-based biotech industry newsletter. He noted one recent example: Last year, five patients with ALL died of brain swelling, known as cerebral edema, in a clinical trial. They had undergone CAR T immunotherapy developed by Juno Therapeutics, a Seattle biopharmaceutical company formed in partnership with Fred Hutch, Seattle Children’s and Memorial Sloan Kettering Cancer Center in New York. (Greenberg and Jensen are two of several cofounders of Juno.)

“This raises questions in the investment community and it does shake the confidence of a lot of people,” says Timmerman. “This is unknown biological territory. We don’t really know how patients are going to respond once a large number of people start getting these drugs, and I think that’s becoming more clear now.” Additionally, Timmerman points out, researchers don’t know what long-term side effects may arise. “T cell therapies don’t behave in the same way in the body as more conventional drugs with half-lives that wash out of the system in a predictable amount of time.”

Greenberg says work on ways to control the robust immune response is “an area of intense investigation.” But he points out that the setbacks in these clinical trials are not a sign of an ineffective treatment, but side effects that will be recognized and, he says, eventually resolved.

“We can’t underestimate the fact that these are real problems. But we don’t want to forget the remarkable clinical signal we have here,” says Greenberg. “Many of the patients on these trials are achieving durable remissions and for the current time, living healthy lives.”