How the discovery of “immune checkpoints” transformed our understanding of cancer immunotherapy
by Hui-Chen Lin
English translation by Wei-Hsin Lin
In 2013, the Cancer Research Institute (CRI) in America designated June as “Cancer Immunotherapy Month” and has since been active in promoting this campaign to increase the public’s understanding of cancer immunotherapy. It’s no accident that it was the CRI that launched this initiative. Established in 1953, the CRI was tasked with the mission of supporting cancer immunotherapy research, not to mention its co-founder, Helen Coley Nauts, is the daughter of William B. Coley, the bone sarcoma surgeon who pioneered cancer immunotherapy.
Dr. Coley noticed that some cancer patients’ tumors would disappear unexpectedly after serious infectious episodes and inferred that the responses to infections mounted by the patients’ bodies must be able to crush cancer cells as well. Therefore, as early as 1891, he started an experiment by injecting bacteria into cancer patients to see how it would affect the tumors. But a lack of convincing results meant a lack of widespread recognition of this therapy which summons our immune system to tackle cancer cells.
In the 1970s, the study of immunotherapy enjoyed a boom. During this period, we also gained a sounder knowledge of the immune system’s complicated functions. Both factors laid a more solid foundation for the development of cancer immunotherapy. However, no matter how many different treatments scientists had attempted, none of them availed. It was not until 1980s and 90s that James P. Allison of MD Anderson Cancer Center and Tasuku Honjo of the Kyoto University discovered the mechanisms of the immune checkpoints, CTLA-4 and PD-1, respectively, and a significant breakthrough in the development of immunotherapy was achieved. It turns out that regulatory cells have an important role in our immune system. While some are responsible for triggering immune responses, the immune checkpoints are found to act like brakes, preventing T cells from over-reacting. Unfortunately, they are also the cracks in the immune system through which cancer cells can escape attacks.
The discovery of immune checkpoints gave us a revealing insight as to how immunotherapy should work. “In the past, we thought tumor cells were allowed to propagate incessantly because immune cells failed to recognize them. So our job had always been to make sure immune cells can identify cancer cells again,” explained Dr. Ann-Lii Cheng, an authority on liver cancer and distinguished professor at National Taiwan University. “But research on immune checkpoints tells us that in fact, the immune system knows which are cancer cells. It’s just that someone hit the pause button and rendered it unable to respond. So we need to find a way to release the button.”
A new battleground of the war against cancer was opened up. Since 2011, immune checkpoint inhibitors have continued to enter the market, the likes of which, such as ipilimumab, nivolumab, pembrolziumab, and atezolizumab, have proven remarkably effective. The large-scale clinical trials led by Dr. Cheng even demonstrated that the combined use of atezolizumab and bevacizumab (used to inhibit the formation of blood vessels in tumors) resulted in the complete disappearance of tumors in 5% to 10% of the patients in the terminal stages of liver cancer and shrank the tumors in another 20% of the patients. About 60% of them managed to keep their cancer in remission after they kept taking the medicine. Though these drugs only produced positive responses in a minority of patients, they undoubtedly prolonged the lives of people who otherwise could have died anytime from their illness.
Dr. Allison and Prof. Honjo’s contributions to the basic research and drug development in this field won them the 2014 Tang Prize in Biopharmaceutical Science and the 2018 Nobel Prize in Physiology or Medicine. Their pioneering work helped remove major obstacles in the study of immunotherapy, a study that has been gestating for over a century and didn’t create much buzz for decades while progressing at a snail’s pace. Campaigns such as the “Cancer Immunotherapy Month” also gave the public a chance to appreciate the fruits of many researchers’ hard work. But it’s only the beginning of the story. So far, about 70% of patients still don’t seem to respond to this type of inhibitors. Thus, Prof. Honjo used his Tang Prize grant to search for ways to make the measurement of all kinds of immune checkpoints more accurate as well as find biomarkers for the indication of positive responsiveness, such as molecules associated with mitochondrial activation, so as to enhance the efficacy of the treatment. Nevertheless, Dr. Cheng admitted that after the combination of bevacizumab and atezolizumab turned out to be so powerful in treating liver cancer, his team has tried many different therapeutic approaches that joined together chemotherapy, targeted therapy and immunotherapy. Yet until now, none of them can surpass the success of that combination. For Dr. Cheng, “it feels like we hit the wall again.”
From a medical point of view, “if this whole field is a scale from 1 to 100, what we have seen so far stands at 1. It means there is another 99% for us to explore. Maybe someday we will be able to completely defeat cancer,” Dr. Cheng noted. He reminded us that since there are more than two immune checkpoints and T cells are not the only immune cells, scientists have started to direct their attention to the uncharted territory, hoping one day they will overcome the hurdles lying ahead.
1.Hui-Zhen Lin is a contributor for the Scientific American. She obtained an MA degree from National Taiwan University’s Department of Animal Science and Technology, and has an MA degree in Science, Health & Environment Reporting from NYU’s Journalism Institute.
2. This article is the outcome of a project collaboration between the Tang Prize Foundation and the Scientific American. The opinions expressed here are the author’s own.