The Promise of Cancer ImmunotherapyThe 2017 Moment Genetics Guide
In 2010, Rob Densen’s wife was diagnosed with Stage 4 lung cancer. The doctors gave her 36 weeks to live, but she lived for 40 months. “She had a genetic mutation for which there was a targeted therapy,” says Densen. “We got that time because 10 or 15 years earlier, some family or foundation or corporation had invested in the development of the basic platform science. So I feel deeply the obligation to pay back.”
Now Densen is president of the Israel Cancer Research Fund (ICRF), a non-profit organization dedicated to raising money for Israeli scientists. This summer, the ICRF partnered with the Cancer Research Institute (CRI), which for decades has championed immunotherapy, an approach to cancer treatment that harnesses a patient’s own immune system to fight the disease. In recent years immunotherapy has delivered stunning results for patients with very advanced cancers, and the pace of progress is accelerating. It was voted “Breakthrough of the Year” by Science in 2013 and saved President Jimmy Carter’s life in 2015. There are currently more than 1,400 clinical trials in immunotherapy worldwide, up from 400 five years ago. “There’s definitely a sense that there’s an unprecedented level of excitement around the potential,” says Brian Brewer, director of communications at the CRI.
Brewer dates this heightened attention to the 2011 American Society of Clinical Oncology conference in Chicago. When an audience saw the impact of a newly approved drug on the survival rates of patients with metastatic melanoma, “there was an audible gasp,” he remembers. The drug was ipilimumab: It was the first so-called “checkpoint inhibitor” to be approved by the FDA and the first new treatment approved for advanced melanoma in more than a decade. Ipilimumab works by blocking access to a molecular off-switch (“checkpoint”) that cancerous tumors can use to disable cells of the human immune system. A 2010 study of the drug found that it increased survival to the two-year mark by 9.8 percent.
Approximately 30 percent of patients respond well to immunotherapy, and drugs for more than 40 cancers are currently in testing. “In certain cancer types, like lung cancer or metastatic melanoma, immunotherapies have had a sort of miraculous impact,” says Densen. “It’s helping people with dire prognoses and giving them incredible help and in some cases, long lives.”
One in three American women and one in two American men will be diagnosed with cancer during their lifetimes, according to the American Cancer Society. There are more than 100 kinds of cancer, and every one of them interacts with our immune systems. “The way the immune system works is it needs to detect a signal of some kind, it needs to recognize a molecule, or a pattern, in order to determine if something is self versus non-self,” says Brewer. “And if it’s non-self then it’s dangerous, and needs to be targeted for destruction.”
Our immune systems do target cancer, but some cancers mutate in ways that allow them to cloak themselves from our bodies’ defenses. The goal of cancer immunologists is to tear away that cloak. “The basis of all the different immune therapies,” says Zvika Granot, developmental biologist at Hebrew University, “is to expose the cancer once more and make it available for immune eradication.” Granot focuses on a type of white blood cell called neutrophils. “We now know that neutrophils may play very different roles in cancer, fighting the disease or promoting it,” he says.
Israeli researcher Vered Padler-Karavani studies the role of sugars in life science, such as those that coat all human cells. In her Tel Aviv University lab, she has discovered an important difference between the sugar coatings of regular human cells and those of tumors: a single atom. “Although it’s just a single oxygen atom, the immune system in humans detects this non-human sugar as foreign, and actually generates antibodies against it. This gives investigators a new handle to attack cancer in the form of antibodies.”
The immunotherapies with the best proven track record so far are checkpoint inhibitors (like ipilimumab), which can be effective against melanoma, lung cancer and other cancers caused by carcinogens; CAR T-cell therapy, which was pioneered by Zelig Eshhar at the Weizmann Institute and works by genetically modifying immune system cells to target a patient’s specific tumor, and can be effective against leukemia and lymphoma; and preventive vaccines for carcinogenic viruses such as HPV and hepatitis. Other treatment avenues are still in development, including therapeutic cancer vaccines designed to target tumors and off-the-shelf antibodies that can be prepared in bulk without customizing therapies for each patient.
Although immunotherapies are more targeted than chemotherapy and radiation treatments, they can have side effects. “The immune system is extremely powerful, and when it becomes highly active it can result in autoimmune disorders,” says Brewer. These can include mild symptoms such as rash, diarrhea and fatigue as well as more serious ones such as colitis and fatal allergic reactions.
And costs for these new treatments are high. Checkpoint inhibitors have list prices near $150,000 per year, and combinations of the drugs that have proven effective can cost more than $250,000. “Like any drug new to the market, the price is pretty steep,” acknowledges Brewer. “Of course, people’s lives are at stake here, so there are a lot of conversations happening to determine what can be done.” One way for cancer patients to access cutting-edge research is to join clinical trials.
“Immunotherapy is the way of the future,” says Densen. “It’s not just about the science; it’s about our obligation as Jews to support it on behalf of all humankind. Tikkun olam doesn’t mean support your family, or support your neighborhood, or even support your co-religionists. It’s heal the world, and cancer is the scourge of all humankind.”