I think we’re in universal agreement when I say that we look forward to football season largely because it means Nobel season is right around the corner, right? And with the first Nobel Prize of 2018, we’ve got the latest Nobel Prize affiliated with UC Berkeley. The Nobel Prize in Physiology or Medicine was awarded on Monday morning to Dr. James P. Allison and Dr. Tasuku Honjo for development of techniques that direct the immune system to attacking cancerous tumors. This year’s #NobelPrize constitutes a landmark in our fight against cancer. The discovery made by the two Medicine Laureates takes advantage of the immune system’s ability to attack cancer cells by releasing the brakes on immune cells. pic.twitter.com/2mppP3NT19 — The Nobel Prize (@NobelPrize) October 1, 2018 The immune system—much like Evan Weaver or Jordan Kunaszyk—is great at attacking and punishing invading pathogens or bacteria that are trying to make us sick. But it sure would be terrible if in practice, these two destroyed our whole offense with their tackles, right? Similarly, our body wouldn’t function at its peak if our immune system were constantly attacking itself (and such autoimmune disorders are a problem in their own right), so our cells have systems in place to keep the immune system from attacking ourselves—think of non-contact jerseys for quarterbacks. Allison discovered an antibody (named ipilimumab and sold as Yervoy) that binds to certain receptors (CTLA-4) on immune cells; when the antibody binds to the cell, the cells are activated and start attacking tumor cells. The analogy being made in media is that Allison’s discovery is like releasing the emergency brake in a car. Although Allison is no longer affiliated with Berkeley, this research was conducted while Allison was a Berkeley professor, so I think it’s more than fair to attribute this award in part to Cal. Allison adores Cal and his time here: “I don’t know if I could have accomplished this work anywhere else than Berkeley. There were a lot of smart people to work with, and it felt like we could do almost anything. I always tell people that it was one of the happiest times of my life, with the academic environment, the enthusiasm, the students, the faculty.” Allison was first introduced to this lovely environment when he joined the faculty in 1985 as a professor of Molecular and Cell Biology and Director of the Cancer Research Laboratory, but ultimately left the university to move to “New York to be closer to the drug companies shepherding his therapy through clinical trials” in 2004. “Berkeley was my favorite place, and if I could have stayed there, I would have. But my research got to the point where all the animal work showed that checkpoint blockade had a lot of potential in people, and working with patients at Berkeley wasn’t possible. There’s no hospital, no patients.” The news article linked above goes into a deep dive of the story of Allison’s discovery (without going too deep into the science, for those of you who made the right decision to not waste your lives on it), so I recommend you check it out. I stole the following video from that site and it features Allison and other Cal faculty, has a nice explanation of his discovery, and extols the greatness of Cal (along with an odd use of the word “frothing”). For his discovery, Allison has already won the 2015 Lasker Award, recognizing “major contributions to medical science” and has now been recognized with the Nobel Prize. Going off the always-reliable Wikipedia, this is the 105th Nobel Prize affiliated with Cal. The University’s count is a little stricter—alumni, current faculty, or deceased winners who retired as Berkeley faculty. Personally, I think the place where the discovery was made is quite a worthy criterion, perhaps moreso than current faculty with the research performed elsewhere. Especially since Allison evidently adores Cal so.<doc-sep>The Nobel Prize in Physiology or Medicine was awarded on Monday to James P. Allison of the United States and Tasuku Honjo of Japan for their work on unleashing the body’s immune system to attack cancer, a breakthrough that has led to an entirely new class of drugs and brought lasting remissions to many patients who had run out of options. Their success, which came after many researchers had given up on the idea, “brought immunotherapy out from decades of skepticism,” said Dr. Jedd Wolchok, a cancer specialist at Memorial Sloan Kettering Cancer Center in New York. It has, he said, “led to human applications that have affected an untold number of people’s health.” Before Dr. Allison’s and Dr. Honjo’s discoveries, cancer treatment consisted of surgery, radiation, chemotherapy and hormonal treatments. A statement from the Nobel committee hailed their accomplishments as establishing “an entirely new principle for cancer therapy.” The drugs based on their work belong to a class called checkpoint inhibitors, with tongue-twisting names that have nonetheless become familiar to many patients. The first ones approved were ipilimumab (brand name Yervoy), nivolumab (Opdivo) and pembrolizumab (Keytruda). Others have since come to market.<doc-sep>This morning, the Nobel Prize committee awarded the 2018 Nobel Prize in physiology or medicine to two scientists who, separately, discovered proteins that “brake” the immune system — work that paved the way for what the committee calls “an entirely new principle for cancer therapy.” The winners are James P. Allison of the United States and Tasuku Honjo of Japan. The FDA has approved cancer treatments based on Allison and Honjo’s work Working in the 1990s, both scientists studied proteins that regulate the immune system and keep it in check. For Allison, this protein was CTLA-4 protein, while Honjo studied a protein called PD-1. Both CTLA-4 and PD-1 regulate the immune system and keep it from being too aggressive. Therefore, it’s possible to use an antibody to target these proteins and shut them down. When these proteins are shut down, and the brakes “released,” our body’s immune system can go on the attack against cancerous tumors, a form of treatment today called immunotherapy. (Both proteins brake the immune system, just in different ways.) In later experiments, Allison found that blocking CTLA proteins in mice cured them of cancer. In 2011, the US Food and Drug Administration approved this method to treat metastatic melanoma. Three years later, the FDA approved Keytruda and Opdivo, two treatments for melanoma that were based on Honjo’s work. The Nobel citation notes that a combination therapy targeting both proteins could work even better. Dr. Allison, 70, is the chairman of immunology at the University of Texas MD Anderson Cancer Center. Dr. Honjo, 76, is a longtime professor at Kyoto University. The two will share the roughly $1.01 million prize money.<doc-sep>James Allison knew he was onto something: He and colleagues had found a compound that acted as a brake on immune system cells called T-cells. His colleagues wanted to investigate this protein as a gateway to treating autoimmune diseases such as rheumatoid arthritis. But Allison had another target in mind: cancer. What if you could uncloak cancer cells so the immune system could go after them? Allison, now at the MD Anderson Cancer Center in Houston, won the Nobel Prize in Medicine for his work on Monday, alongside Japan’s Tasuku Honjo. Their findings have led directly to the development of Yervoy, the first immunotherapy drug to hit the market for cancer, as well as Keytruda, the drug credited with keeping former President Jimmy Carter alive after his melanoma diagnosis. These drugs have transformed how cancer is treated and given hope to people with some of the most devastating cancer diagnoses. The drugs, most of which cost $100,000 or more for a course of treatment, are also making big money for pharmaceutical companies. But Allison struggled to get businesses interested in his discovery, said his longtime friend and fellow cancer researcher Lewis Lanier. “When he found it, he knew what he found,” Lanier, who studies cancer immunotherapy at the University of California, San Francisco, told NBC News. “He really wanted to make this help people, not just cure mice,” Lanier added. “Pharma (companies) thought, ‘Well, immunology’s really nice but we’re going to work on autoimmune disease.’ Jim kind of flipped it and said, ‘I want to induce the immune system to get cancer.’” BREAKING NEWS The 2018 #NobelPrize in Physiology or Medicine has been awarded jointly to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” pic.twitter.com/gk69W1ZLNI — The Nobel Prize (@NobelPrize) October 1, 2018 That was, in no small part, because Allison had personal experience with cancer. His mother, his brother and two uncles died of cancer. Allison’s work focused on cytotoxic T lymphocyte antigen-4 or CTLA-4, which tamps down the activity of T-cells. Controlling T-cells can be a good thing. Out-of-control immune cells can produce what’s called a “cytokine storm”, a deadly result of some infections, as well as autoimmune diseases such as type-1 diabetes, multiple sclerosis and rheumatoid arthritis. However, tumor cells can exploit this mechanism to escape the immune system as it protects the body against not only germs, but cancer as well. “After helping to show that CTLA-4 functions as a ‘brake’ on T cells and prevents them from exerting their disease-fighting ability, he was the first to demonstrate that blocking CTLA-4 with an antibody could prevent tumor development in mice as well as enable them to eliminate large, established tumors.” The Cancer Research Institute, a New York-based organization that funds cancer research and where Allison serves as head of the scientific advisory council, said in a statement. Similarly, Honjo worked with a protein called PD-1, which slows T-cells via a different mechanism. Interfering with these mechanisms is called checkpoint blockade, and it has spawned a whole generation of new cancer therapies, which can have spectacular results in a small subset of cancer patients. Carter was one of them. He was already in his 90s when he was diagnosed with melanoma that had spread to his brain. But surgery and a few rounds of Keytruda soon had him back on his feet and back doing the charity work that has been his passion since leaving office. Big Pharma did not at first see the same promise in these drugs that Allison did. They thought it was too risky. “Allison fought passionately to translate his findings into medicine for human patients," the Cancer Research Institute said. Even as Allison showed the potential benefits of using a monoclonal antibody, a lab-generated silver bullet designed to block CTLA-4, “many experts questioned whether anti-CTLA-4 could ever be successfully used in humans,” the University of California Berkeley, where Allison did some of his work, says in its history of cancer immunotherapy. But the ideas of Allison and Honjo were making waves in the then small world of immunotherapy. Through a series of personal connections, the work caught the attention of Medarex, a small biotech founded by scientists interested in harnessing the immune system. "Jim's major concern was he was very impatient because he really wanted us to go very fast," said Nils Lonberg, a former Medarex executive who is now senior vice president at Bristol-Myers Squibb. "He was frustrated trying to deal with pharma companies but he was also rightly suspicious that we would drag things out." Medarex took on the development of CTLA-4 into a commercial cancer drug. "We thought that Jim's experiment was the nail and we had the hammer," Lonberg said. Medarex also worked to develop one of the first PD-1 inhibitors, a drug called Opdivo. Bristol-Myers Squibb acquired Medarex in 2009 and brought both drugs to the market. It paid off for the drug giant. Ipilimumab, sold under the brand name Yervoy, costs $120,000 for a course of treatment. Opdivo goes for about $150,000 in the U.S. “Without Jim’s persistence, checkpoint blockade would not exist as a new form of cancer therapy,” Lanier said. Yervoy got fast-track approval from the Food and Drug Administration in 2009. “Since ipilimumab’s development, it has been used to treat tens of thousands of patients with advanced melanoma, almost 20 percent of whom have remained alive a decade after treatment — an almost unheard of success rate in a cancer which claims the lives of nearly half of patients within a year,” the Cancer Research Institute said.<doc-sep>
Last year, when Popular Mechanics covered the future of cancer treatment, I said that many of James P. Allison’s contemporaries believed that he would win the Nobel Prize. But to be honest, that was an understatement. People were in awe of him. His work was so brilliant that his name opened doors with other scientists. “Oh,” very important people would say when they found out he had agreed to be interviewed for my story. “So you’ve got the big guns on this one.” "It is an entirely new category of treatment for cancer" The prediction has proved prescient. Today, Allison, who is the chair of the department of immunology at MD Anderson Cancer Center in Houston, won the Nobel prize in Physiology or Medicine along with Tasuku Honjo, a professor in the department of immunology and genomic medicine at Kyoto University in Japan (whom I have not met, but whom I am sure is equally impressive). The two scientists independently discovered pieces of cellular machinery that became the foundation for immunotherapy, a new type of cancer treatment in which doctors convince a patient’s own immune system to attack tumor cells as if they were a bacterium or virus. Here’s how it works: The immune cells called T-cells are devastating killers, attacking anything in the body displaying molecules called antigens that identify it as foreign and potentially threatening. We would be in bad shape if T-cells went crazy and started attacking anything they felt like, so the body has a system of checkpoints in place to prevent them from targeting healthy cells. Cancer, being a unique amalgam of self and non-self, exploits this checkpoint system, pretending to be part of the body to escape the notice of the immune system. Allison and Honjo each discovered a way to shut down the checkpoints using drugs called “checkpoint inhibitors,” which allow a patient’s immune system to rediscover and subsequently destroy cancer cells anywhere in the body. It is an entirely new category of treatment for cancer. Before Allison and Honjo’s work, if you couldn’t cure cancer with surgery, radiation, or chemotherapy, there wasn’t a whole lot else you could do. Now, drugs based on immunotherapy, such as Keytruda, Yervoy, Opdivo, and Tecentriq, have prolonged the lives of hundreds of people with cancers that would be otherwise incurable. Upper left: Activation of T cells requires that the T-cell receptor binds to structures on other immune cells recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA- 4 functions as a brake on T cells that inhibits the function of the accelerator. Lower left: Antibodies (green) against CTLA-4 block the function of the brake leading to activation of T cells and attack on cancer cells.Upper right: PD-1 is another T-cell brake that inhibits T-cell activation. Lower right: Antibodies against PD-1 inhibit the function of the brake leading to activation of T cells and highly efficient attack on cancer cells. Nobel Prize It wasn’t an easy road. Even as late as the 2000s, the field of immunotherapy was not well regarded by other cancer scientists. Many considered trying to turn the immune system against cancer foolish, or even dangerous. “In 2006 I spoke at Cold Spring Harbor and I was the only immunologist speaking—the only immunologist even attending,” Allison told me back when I was reporting the story. “It was frightening. My friends who knew that field said You better watch out because these people hate immunotherapy. They’re gonna kill you.” Obviously, they didn’t. Today, they might even offer him a glass of champagne.