Spotlight on New Cancer Immunotherapy: Ono Pharmaceutical’s Opdivo

Born-in-Japan Cancer Drug

Cancer has been dubbed, among other names, the “emperor of all maladies.” The disease has waged war on humankind for four millennia, and despite all the weapons that we have forged against this sworn enemy, we have yet to declare victory over it. In 2014 alone, as many as 370,000 Japanese lives were lost to the disease.

Cancer cells are atypical cells that have formed from what were once normal cells. Part of the difficulty of treating cancer lies in the fact that its growth is powered by the same mechanism that has made it possible for humankind to flourish on the earth. Cancer cells dodge attacks from the body’s innate immune system and gradually multiply, eventually threatening the very life of their host, and the prolonged battle with cancer drains the immune system over time.

In 2014 a drug based on a new approach to cancer treatment came out in Japan. Hopes are high for nivolumab, sold by Ono Pharmaceutical under the tradename Opdivo, as a breakthrough in cancer immunotherapy. Its development was spearheaded by Honjo Tasuku of Kyoto University (currently guest professor at Kyoto University and chairman of the Board of Directors of the University of Shizuoka), who has been a leader in the international immunological research community for many years.

Building on a Chance Discovery: Removing the Immune “Brake”

As the story often goes, it all started with a chance discovery. In the early 1990s Ishida Yasumasa, now an associate professor at the Nara Institute of Science and Technology, was a graduate student at the Honjo Lab at Kyoto University searching for molecules that initiate programmed cell death (apoptosis) in immune cells. The first molecule that he discovered in 1992 was named programmed cell death 1, or PD-1.

Studies in mice to understand its mechanism led to a curious revelation. PD-1 was shown to be widely expressed on activated immune cells, such as T cells and B cells, and to function as brakes on the immune system, effectively inhibiting the body’s immune response. Molecules that behave like this are known as immune checkpoints. Honjo reported the findings in 1999. He knew then that this mechanism could be applied to treat infections and cancer.

Half a Century of Frustrated Progress

The concept of cancer immunotherapy, also known as immuno-oncology, has been around for over half a century. The Australian immunologist Sir Frank Macfarlane Burnett, who received the Nobel Prize in Physiology or Medicine in 1960, proposed the theory of cancer immunosurveillance in the 1950s. As many as 3,000 cancer cells are born in the human body every day, and Macfarlane purported that the immune system kills these cells to prevent them from growing into tumors. For many decades, however, the phenomenon went unproven.

Researchers who support the theory have worked to develop treatments that suppress cancer by activating the immune system. Yet they have fallen short of achieving satisfactory results. This comes as no surprise to Honjo; an immune response is ignited when the body detects the presence of an antigen, but positive costimulation is needed to rev up the immune engine.

The basic principle of conventional cancer immunotherapy is to find cancer-specific antigens and boost immune response by injecting them into the body. But when the subject already has cancer and the body is heavily loaded with the same antigen, adding a few extra milligrams is bound to be rather futile. And if there is negative costimulation to boot, no amount of pumping the gas will activate an immune response. This “brake” needs to be removed in order to reactivate the immune system and begin treating the cancer. As a front-runner in immunology, Honjo knew that the key lay there.

Meanwhile, James Allison of the University of Texas discovered that another molecule called cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) also acts as a brake on immune cells. Allison reported in 1996 that antibodies that block CTLA-4 function wiped out tumors in mice.

PD-1 Blockade Cures Cancer in Mice

In 2000 and 2001 joint studies by Kyoto University and US institutions, including the Genetics Institute, resulted in the discovery of two proteins that bind specifically to PD-1, called programmed cell death ligands 1 and 2 (PD-L1 and PD-L2). When PD-L1 is present on the surface of a cancer cell and binds with the receptor PD-1 on the surface of an immune cell, the immune cell is suppressed and loses its ability to attack cancer cells. Preventing this from happening through the use of an anti-PD-1 antibody will undo the brake, giving the immune cells a fighting chance.

The Honjo Lab conducted animal experiments and discovered that PD-1 blockade in mice dramatically strengthened their defense against cancer. The results were published in 2002. The team also conducted a variety of experiments to augment the data on the antibody’s role in suppressing metastasis of transplanted cancer.

At the same time, they sought ways to put their findings to practical use. But Kyoto University lacked the know-how for patent application at the time, so Honjo asked Ono Pharmaceutical, with which he had had personal ties since his days with his former mentor, to be a joint applicant. In 2002 Honjo and Ono Pharmaceutical filed a provisional application for a method-of-use patent for PD-1-based immunotherapy.

Confident that anti-PD-1 antibodies could be used to develop cancer drugs, Honjo approached numerous pharmaceutical firms in Japan. He was initially met with skepticism about cancer immunotherapy at every turn, and not a single company said yes, not even Ono Pharmaceutical. Turning his eyes overseas, Honjo then sounded out a US venture company and received an enthusiastic response. When he told Ono Pharmaceutical about this, it made a last-minute decision to take on development of the drug. The company’s change of heart is said to have been because it was contacted by US biotechnology firm Medarex, which held the patents and technology for creating human antibodies, about developing clinical applications for the anti-PD-1 antibody.

The human anti-PD-1 antibody nivolumab was approved by the US Food and Drug Administration as an investigative new drug in 2006, and clinical trials began in the United States the same year. Development picked up steam after US pharmaceutical giant Bristol-Myers Squibb acquired Medarex in 2009 for $2.4 billion.

The Birth of Opdivo in 2014

The US clinical trials involved administering the drug to patients with solid tumors, including non-small-cell lung cancer, prostate cancer, colorectal cancer, and renal cell cancer, as well as malignant melanoma. The drug was found to be effective on all of these cancers. The response rate—the percentage of patients whose tumors either shrunk or disappeared—was close to 30% for melanoma and renal cell cancer. The test results were reported in 2012 in the New England Journal of Medicine, one of the world’s most prestigious medical journals, and an editorial noted that the drug had yielded the highest response rate among the many cancer immunotherapies that have been tried out over the past three decades. Some of the patients stayed in remission for longer than a year after treatment.

Meanwhile, in Japan Ono Pharmaceutical conducted a phase I trial on patients with non-small-cell lung cancer and renal cell cancer, among other tumors, to determine the drug’s safety and observed significant responses in several cases. Ono prioritized development of the drug for melanoma, which has the worst prognosis among the cancers tested. It was the first time in two decades that a phase II trial was conducted in Japan for melanoma.

The US magazine Science named cancer immunotherapy using antibodies the 2013 “Breakthrough of the Year.” Nivolumab was approved for the treatment of melanoma under the tradename Opdivo first in Japan in July 2014 and then in the United States in December of that year. In addition, after the successful completion of trials, the drug received approval in the United States in March 2015 for use on lung cancer (previously treated advanced squamous cell cancer).

Ono Pharmaceutical’s Opdivo (from the company’s press release).

More clinical trials are underway for a number of other cancers, and approved use of the drug is expected to expand over the coming months. Pharmaceutical companies around the world are also developing various drugs that target immune checkpoints of one kind or another.

In 2011 Bristol-Myers Squibb obtained FDA approval for ipilimumab, an anti-CTLA-4 antibody. Both CTLA-4 and PD-1 are immune checkpoint molecules, but they inhibit different aspects of the immune system, and using the two drugs in combination dramatically improves the response rate. Honjo and Allison were named joint recipients of the first Tang Prize, inaugurated in Taiwan in 2014 as the “Nobel Prize of the East,” in biopharmaceutical science. (The laureates received NT$50 million, or roughly US$1.5 million, in prize money.)

Low in Side Effects, High in Cost

Nivolumab sets itself apart from conventional counterparts in several significant respects. It can be applied to any cancer, and there are few side effects. It will continue to be effective once a patient responds, even if the cancer is advanced, and can be administered repeatedly. Unlike targeted therapies, which zero in on molecules involved in the growth of specific kinds of cancer, immune checkpoint inhibitors can treat a wide range of cancers. Honjo predicts that the day will come when conventional cancer drugs are hardly used and all cancers are treated with PD-1 antibodies.

The biggest drawback of Opdivo is its steep price tag. The cost of treating a patient is estimated to average about ¥15 million per year. But targeted therapies are expensive in their own right, and they have a short window of time before mutation of the cancer cells renders them ineffective. Considering that nivolumab has been shown to partially or completely wipe out cancer cells in many patients, its price is not necessarily outrageous. In Japan, if the treatment is covered by insurance, out-of-pocket expenses for the patient will be kept down thanks to the high-cost medical care benefit system. For the nation’s already tight finances in healthcare insurance, though, it will be a heavy load.

The biggest outstanding issue with nivolumab is that, while some patients respond so well that they no longer need to take the drug, others do not respond at all. Some of the work-arounds being considered are to begin treatment earlier and to develop markers to determine whether or not the treatment will have an effect on the patient.

Generating a Virtuous Cycle Between Basic and Clinical Research

Nivolumab is the outcome of a smooth transition from basic to clinical research, with the university providing not only the original concept but also the idea for the proof-of-concept study—the initial clinical study to test the feasibility of a product concept.

On April 1, 2015, the Japan Agency for Medical Research and Development (AMED) was launched as a centerpiece of the third “arrow” of Prime Minister Abe Shinzō’s Abenomics program, defined as a growth strategy that encourages private investment. The level of basic research in Japan is far from inferior to those of other countries, as exemplified by research on induced pluripotent stem cells, or iPS cells. But Japan’s challenge has been the lack of a robust framework for translating basic research findings into clinical practice. AMED was established as an organization that consolidates the budget for medical research and development and promotes practical applications in accordance with the progress of research. It is said to be modeled after the US National Institutes of Health.

“Medical innovation in Japan is a one-way ticket, and the policy measure is insufficient,” points out Honjo, who spent several years as an NIH fellow. “We need a system that funnels the profits made by pharmaceutical companies back to universities. Only then can there be a virtuous cycle in which people grow and the seeds of new research are sown.”

When world-class pharmaceutical companies and universities are able to build genuine win-win relationships, we will be one step closer to saving the lives that are being lost to cancer.