The two Nobel Laureates in Physiology or Medicine 2018, James Allison and Tasuku Honjo, independently discovered that the reactivation of the immune system by blocking two major negative regulators, CTLA4 and PD-1, can cure a significant portion of cancer patients.

“As a result, Jim and I have experienced many occasions that have made us feel well rewarded, such as meeting cancer patients who say their lives were saved by our therapies,” stated Honjo in his Nobel banquet speech on December 10th 2018.

Never forget what you really want to do

But Tasuku Honjo did not set out to discover a cure, or a therapy. “I never expected my research working on the immune system would lead to the cancer therapy,” he said in an interview with Nobel Media right after the Nobel announcements.

When he and his colleagues first isolated PD-1 they did not know what the function of this molecule would be and it took them almost ten years to realize its important function in regulating the immune system.

Honjo has in previous interviews both emphasized the importance of persistence and of performing basic science. And he advises young scientists to follow their curiosity.

”Sometimes, a direct attack may be difficult. You can take a round route or a side tour but never forget what you really want to do,” he says.

What Honjo and his colleagues were able to show, through persistence and performing basic research, was a checkpoint protein (PD-1) in T cells that acts as a type of “off switch” to help the T cells from attacking other cells. Later, drug developers came up with medicines to target those brakes. Those drugs, such as Keytruda and Opdivo, are now widely used drugs to treat many different types of cancer.

From space to medicine

Tasuku Honjo was born right in the middle of the ongoing World War II, in 1942 in Kyoto, Japan. There were a lot of medical doctors among his family members and his father was a surgeon. But his first fascination for natural sciences was space. At the playground at his elementary school he watched the tiny ring of Saturn through the telescope.

“The telescopic view of Saturn fascinated me. I dreamed of becoming an astronomer,” he said during his Nobel lecture. He read many books and strongly wanted to become an astronomer. But his enthusiasm gradually faded when his mother gave him a book, a biography, about Hideyo Noguchi (1876–1928). Noguchi, a prominent Japanese bacteriologist, identified Syphilis spirochete as the cause of progressive paralysis and he was one of the first Japanese scientists to ever gain worldwide renown. In his journeys to Accra (now Ghana), as part of an expedition, he contracted yellow fever.

“I was impressed by his strong spirits and his pioneering activities,” says Honjo. So he started to study medicine at his hometown university.

He says that there he was fortunate to meet Osamu Hayaishi, a world-renowned biochemist and oxygenase scientist. He inspired Honjo in his studies and became his mentor, and he also brought an international atmosphere to the university, Honjo recalls.

After finishing his MD at Kyoto University in 1966, Honjo became a fellow at the Carnegie Institution, Department of Embryology, in Washington and Baltimore, USA (1971–1973), and Visiting Fellow and Associate of National Institute of Child Health and Human Development at NIH, USA (1973–1974). During his time at the Carnegie Institute in Baltimore Honjo met Donald Brown, who inspired him to work in the field of molecular immunology.

Honjo received his PhD from Kyoto University in 1975 and during 1974–1979 he was an Assistant Professor at the Faculty of Medicine at the University of Tokyo. Thereafter he spent five years as Professor at the School of Medicine at Osaka University and in 1984 he returned to the University of Kyoto, where today he is Deputy Director-General and Distinguished Professor at Kyoto University Institute for Advanced Studies (KUIAS).

The beginning of an era

In his Nobel lecture Tasuku Honjo spoke about the findings about the immune response, and up until the 1970s there was still a lot of mystery about it and scientists where trying to understand how animals can generate antibodies specific to an almost infinite number of antigens, including artificial chemicals. In 1970 the structure of an antibody was identified and the same year Sir Frank Macfarlane Burnet proposed the theory of immune surveillance against cancer, but numerous attempts to develop immunotherapy were unsuccessful.

During the years to come, however, more and more pieces of the puzzle were laid. And, as mentioned above, Honjo discovered an important protein on immune cells in 1992, PD-1. He explored its functions over many years and eventually revealed that it operates as a brake on the immune system. He was able to show how a strategy to inhibit the brake can be used in the treatment of cancer, and in 2012 a key clinical study showed clear efficacy in treatment of cancer patients.

His findings meant a paradigm shift in cancer therapy and what is now known as immune checkpoint therapy has fundamentally changed the outcome for patients with severe forms of advanced cancers. Today more than 1 000 clinical trials have shown anti-PD-1 treatment to be effective for a wide range of tumors. It has also shown to have less adverse effects because normal cells are unaffected, and it has shown to have durable effects for respondents after stopping treatment.

”I believe this is the beginning of a new era in cancer treatment. I hope many people in the world will study further to improve cancer immunotherapy by combinations with other chemicals or even with other type of treatments. I believe cancer immunotherapy will be the Number One choice in the future,” he says when I ask about his hopes for the future of immune checkpoint inhibitors.

A chronic disease

Tasuku Honjo showed a slide in his Nobel lecture that stayed in my mind. It showed the future prospects in cancer therapy, from 2016, when efficacy of PD-1 blockade therapy was improved and most cancers were still treated by surgery and chemotherapy, through to 2020, when many more cancers may be treated by immunotherapy, with the amount of anti-PD-1 treatments being 50 percent of the treatments. The slide finished by showing 2030 (or someday Honjo said), when cancer may be controlled by immunotherapy to become one of the chronic diseases (where anti-PD-1 treatment is the majority of treatment), when patients can have tumors but the tumor growth is stopped and the patient can retain their quality of life.

Another hopeful slide that really illustrated the impact of Honjo’s discovery showed a clinical study from 2015 (J. Hamanishi et al., J. Clin. Oncol.), in which a 60-year old female patient with clear cell ovarian cancer had been treated with nivolumab (an inhibitory antibody for PD-1). She responded quickly and became completely tumor free, and after one year they stopped treatment and she has then remained tumor free for four years.