Scanning electron micrograph of a human T-cell from the immune system of a healthy donor. Image credit: National Institute of Allergy and Infectious Diseases (NIAID)
What if the body could heal itself of even the most aggressive and deadly tumors?
In the span of a few years, the idea has gone from New Age notion to medical reality.
Researchers are investigating the potential of immunotherapy to be a powerful, effective and long-lasting solution to kill cancer.
One of the confounding characteristics of cancer has long been that the body’s usually active patrol against viruses tends to leave deadly cancer cells alone to fester, mutate and spread.
The immune system has this blind spot by design – an immune system that has an ability to attack itself leads to autoimmune diseases, so as protection, it screens out its own tissue.
T-cells (stained in pink and brown), which are used by the immune system to fight disease, show an increase near prostate cancer cells following an immunotherapy treatment. Image credit: Fong lab/UCSF
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For decades, scientists assumed that cancer was beyond the reach of the body’s natural defenses. But after decades of skepticism that the immune system could be trained to root out and eliminate these malignant cells, a new generation of drugs is proving otherwise.
The treatment consists of infusing antibodies that enhance the immune system to recognize cancer cells and attack it. What’s more, since the immune system has a built-in memory, it continues to go after cancer cells, so the response can be longer lasting and more complete.
The trick is that this treatment doesn’t work for everybody, and researchers don’t yet understand why. But when it does work, the results have been particularly impressive.
"Although there is a 30-year history of people and institutions trying to develop immunotherapy approaches to cancer, it has only been in the last 10 years that we’ve broken through and have been able to impact cancer using immunotherapy," said Jeffrey Bluestone, PhD, executive vice chancellor and provost of UC San Francisco.
"I do think that we’re at an inflection point with immunotherapy," he added. "It will be revolutionary and will impact how we approach cancer for years to come."
The Last Hope
Patricia Hollowell, 80, was diagnosed with melanoma in April 2012.
She had three surgeries in quick succession in her hometown of Grand Junction, Colo., that removed the tumors from her head but didn’t prevent them from coming back and spreading quickly to her neck and lymph nodes.
On the day she returned home from the hospital after the third surgery in June of that year, her husband had a massive stroke and died a week later.
"It was the summer from hell, it was like everything was over," she recalled. "When my husband died and my cancer came back it was like the world was over, my world was over. It was just complete devastation."
This was not Hollowell’s first bout with cancer, having survived breast and colon cancer 30 years ago. This time, after the failed surgeries and with her cancer spreading quickly, she figured her luck would run out.
Her doctors suggested her only hope might be to join a clinical trial involving new cancer immunotherapy drugs.
Hollowell moved to San Rafael, Calif., to be with her daughter and was accepted into a trial at UCSF under the direction of Adil Daud, MD, director of melanoma clinical research at the UCSF Helen Diller Comprehensive Cancer Center. She began a biweekly IV of an antibody that targets an immune inhibitor called PD-1 in June 2013.
"Within a month, my doctors could see the difference, and I am now tumor-free," she said. "For me, it’s been an absolute miracle."
Daud said use of the PD-1 antibody has been "a game-changer for melanoma therapy." Just a few years ago, about 10 percent of his patients saw their tumors shrink with immunotherapy treatment; today the response rate has improved to 30 to 50 percent. That’s compared to chemotherapy treatment, which has a 10 percent response rate and can be a short-lived solution.
Immunotherapy is "not a sure thing even now, but a positive response is becoming a lot more likely with [the antibody for] PD-1," Daud said. "Hopefully it will become a building block, and we will add to it and go beyond a 50 percent response rate in the coming years."
For Hollowell, twice-monthly trips to UCSF for treatment could soon end if her PET scan at the end of February shows no present tumors.
"I feel really good," she said. "The only bad part is that I’m a little tired, so I rest during the day, but the good part is I’m alive."
Treating the Patient Instead of the Disease
"For the longest time, people did not believe this was possible," said Lawrence Fong, MD, associate professor of medicine at UCSF and one of the University’s lead investigators in the expanding use of immunotherapy.
Lawrence Fong, MD, and Jera Lewis, a staff research associate in Fong's lab, pull cryopreserved patient samples stored in a liquid nitrogen tank to assess for immune responses. Photo by Susan Merrell
Cell cultures containing growing tumor cell lines are stored in Fong's lab. Photo by Susan Merrell
"Now we can treat cancer by treating the patient instead of the disease," he said. "That’s the biggest change. We can treat cancer without delivering chemotherapy or radiation to kill the cancer or performing surgery to get rid of the tumor."
Researchers at UCSF and elsewhere have identified cell receptors, such as CTLA-4 and PD-1, which act as a brake on the immune system, limiting its response.
With the use of antibodies to inhibit these blockade receptors, allowing a more active and vigilant immune system, doctors have seen outstanding responses in patients with metastatic melanoma and lung cancer, both of which are almost always fatal with conventional treatments. Immunotherapy also has been successful in cancers of the bladder, prostate, kidney and bone marrow.
"This was a radical idea: that the body already possesses the ability to defeat cancer, and that medicine’s role was to find a way to allow the body to marshal the healing work it is naturally capable of," Fong said. "We all believed it could work, but very few would have predicted the 180-degree change that we’ve seen over the last two years."