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Nobel winner Honjo's work on immune response opened new frontier in cancer treatment

Tasuku Honjo (Mainichi/Yusuke Komatsu)

OSAKA -- Tasuku Honjo, distinguished professor at Kyoto University, has won this year's Nobel Prize in physiology and medicine for his discovery of a protein responsible for suppressing immune response.

The PD-1 protein that Honjo discovered has led to a breakthrough cancer immunotherapy, and earned him the U.S. journal Science's "Breakthrough of the Year" prize in 2013. Expectations are high for further research and development of anti-cancer therapies as the disease continues to be a serious health threat.

Immunotherapy is an ideal treatment in that, when successful, it uses the patient's own immune system to kill their cancer. Many researchers have tried to develop cancer immunotherapies, including by marking cancer cells with antigens to prompt the immune system to attack them, but none produced the desired results.

One of the factors contributing to these past failures was the presence of the PD-1 protein on the surface of T cells, a type of lymphocyte that helps control immune response. When the PD-L1 protein on the surface of a cancer cell binds to the PD-1 protein, this signals the T cell to hold back its attack and puts the brakes on the immune response to the cancer. Even if antigens are injected to activate the immune system, the PD-1 protein works to suppress immune function.

It was just these kinds of mechanisms that Honjo and his joint Nobel laureate, University of Texas professor James Allison, decoded. The discovery opened the way for Osaka-based Ono Pharmaceutical Co. to develop the anti-cancer medication nivolumab, sold under the trade name Opdivo, which was released in September 2014. The drug is designed to combine with the PD-1 protein to inhibit it from binding to PD-L1, taking the brakes off the immune system and thus enhancing its ability to attack cancer cells.

Of 35 malignant melanoma patients who participated in a drug trial ahead of nivolumab's approval, eight saw their tumors shrink six months after they began the treatment course, while progression of the cancer was halted in 15 others. An Ono Pharmaceutical representative commented, "It is a drug that can suppress cancer's progress, possibly allowing patients with the disease to lead an ordinary life."

Keio University professor and tumor immunology specialist Yutaka Kawakami, who heads the Japanese Association of Cancer Immunology, commented, "The drug has a significant impact in that it has made immunotherapy a pillar of cancer treatment. It is also epoch-making in that the drug, if it proves effective, can enhance patients' long-term survival rates."

Apart from the PD-1 protein, there are other T-cell surface proteins that act as checks on the immune system. One such protein called CTLA-4 was discovered by professor Allison. Ipilimumab, a drug designed to inhibit the work of CTLA-4, has hit the market under the trade name Yervoy and has been hailed as a groundbreaking immunotherapeutic agent.

While Allison is touted as an immunotherapy trailblazer, Opdivo is said to have fewer side effects than Yervoy. Molecular geneticist Yasumasa Ishida, an associate professor at the Nara Institute of Science and Technology, said, "Mr. Allison was recognized as an (immunotherapy) pioneer, and Honjo was appreciated for his contribution to putting it to practical use."

Ishida was a member of Honjo's lab in 1992 as a graduate student and discovered the PD-1 protein through a unique gene hunt. While the function of PD-1 was still unknown at the time, subsequent research by another student led to speculation that the protein had a role in regulating immune response. This inspired Honjo to believe that the discovery could lead to the development of an effective medication.

Further research and experiments by Nippon Medical School professor Yoshiko Iwai, then a graduate student, and others showed the possibility that suppression of the PD-1 protein could be effective in cancer treatment. They also succeeded in developing a drug to inhibit the function of PD-1 in humans.

However, Japan's major pharmaceutical firms showed little interest. "No one believed that cancer could be treated with immunity," Honjo recalls. After many twists and turns, including Honjo approaching a U.S. venture, Ono Pharmaceutical and an American drug maker jointly developed Opdivo.

"Because of professor Honjo's belief and passion, our research led to the development of the drug," said Iwai.

As a professor, Honjo has always told the students in his lab, "The best part of research lies in discovering a raw stone before it is cut into diamonds. Try to pick up a raw diamond and make it shine." Honjo himself lived up to his words through the discovery of the PD-1 protein and decoding its function.

(Japanese original by Shinpei Torii and Shuichi Abe, Osaka Science & Environment News Department)

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