Title of Presentation

“Cancer immunotherapy by PD-1 blockade”

PD-1 is a membrane receptor molecule that was accidentally discovered by Ishida et al. in 1992 when they used subtraction hybridization to isolate a cDNA whose expression is induced by cell death in the thymus. After that, Nishimura et al. analyzed PD-1 knockout mice and discovered that PD-1 is an immunoinhibitory molecule. In 2002, Iwai et al. discovered that monoclonal antibodies that block PD-1 signaling activate the immune system and are effective in the treatment of diseases such as viral infections and cancer. In a joint study with the Department of Gynecology and Obstetrics at Kyoto University, we found a remarkable correlation between the prognosis of ovarian cancer and PD-1 ligand expression in tumor cells. This meant that PD-1 ligand expression by a tumor was associated with a poor prognosis, leading the team to hypothesize that these tumors might have some mechanism for avoiding attacks by killer T cells. In light of these findings, we met with a pharmaceutical company to propose that they develop human monoclonal antibodies to treat cancer and convinced the company to start the process.

Through this collaboration, a human anti-PD-1 monoclonal antibody was generated using human antibody production technologies in 2006. Phase I clinical studies of the antibody conducted in the United States and Japan demonstrated the tolerability and efficacy of the antibody in patients with a variety of cancers. To build on these findings, the Translational Research Center at Kyoto University started a phase II clinical study that exclusively enrolled ovarian cancer patients in the winter of 2011. After that, clinical studies continued, and the anti-PD-1 antibody was approved by the PMDA for the indication of melanoma in June 2014. Nearly 200 clinical studies of anti-PD-1 antibodies against various types of cancers are currently being conducted all over the world, and their results demonstrate the efficacy of the antibodies. It will be interesting to see how Japanese companies will aid in the development of the next generation of new drug candidates discovered through academic research in the future.

Profile

Web Site URL

http://www2.mfour.med.kyoto-u.ac.jp/en/

A brief Biography

Professor Honjo was born in 1942. After obtaining his Ph.D. degree from Kyoto University’s Graduate School of Medicine, he worked at the Carnegie Institution of Washington and the National Institutes of Health in the United States as Visiting Fellow. He returned to Japan in 1974 and held various positions such as Assistant Professor at The University of Tokyo Faculty of Medicine and Professor at Osaka University Faculty of Medicine before becoming Professor at Kyoto University Faculty of Medicine in 1984. Since then, he has served as Director of the Center for Molecular Biology and Genetics, Dean of the Graduate School of Medicine, and Dean of the Faculty of Medicine at Kyoto University. After his retirement in 2005, he became Visiting Professor at Kyoto University Graduate School of Medicine. In addition to these positions, he has served as Science Adviser to the Higher Education Bureau, Director of the Research Center for Science Systems at the Japan Society for the Promotion of Science, and Executive Member of the Council for Science and Technology Policy in the Japanese Cabinet Office. He is currently Chairman of the Board of Directors of Shizuoka University, President of the Foundation for Biomedical Research and Innovation, and a member of The Japan Academy.

Details of selected Awards and Honors

1996	The Imperial Prize and the Japan Academy Prize
2000	Award “Persons of Cultural Merit” by Japanese Government
2001	Foreign Associate of U.S. National Academy of Sciences
2003	Member of Leopoldina (The German Academy of Natural Scientists)
2005	Member of Japan Academy
2012	Robert Koch Prize
2013	Order of Culture
2014	Tang Prize
2015	William B. Coley Award
2016	Smalley Award

A list of selected Publications

Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Ishida, Y., Agata, Y., Shibahara, K. and Honjo, T. EMBO J. 11 3887-3895 (1992)

Development of lupus-like autoimmune disease by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Nishimura, H., Nose, M., Hiai, H., Minato, N. and Honjo, T. Immunity 11 141-151 (1999)

Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitsz, L. J., Malenkovich, N., Okazaki, T., Byrne, M. C., Horton, H. F., Fouser, L., Carter, L., Ling, V., Bowman, M. R., Carreno, B. M., Collins, M., Wood, C. R. and Honjo, T. J. Exp. Med. 192 1027-1034 (2000)

PD-L2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation. Latchman, Y., Wood, C., Chernova, T., Borde, M., Chernova, I., Iwai, Y., Malenkovich, N., Long, A., Bourque, K., Boussiotis, V., Nishimura, H., Honjo, T., Sharpe, A. and Freeman, G. Nature Immunol. 2 261-268 (2001)

Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice. Nishimura, H., Tanaka, Y., Okazaki, T., Nakatani, K., Hara, M., Matsumori, A., Sasayama, S., Hiai, H., Minato, N. and Honjo, T. Science 291 319-322 (2001)

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Iwai, Y., Ishida, M., Tanaka, Y., Okazaki, T., Honjo, T. and Minato, N. Proc. Natl. Acad. Sci. USA 99 12293-12297 (2002)

Autoantibodies against cardiac troponin I are responsible for the dilated cardiomyopathy in PD-1 deficient mice. Okazaki, T., Tanaka, Y., Nishio, R., Mitsuie, T., Mizoguchi, A., Jian, W., Ishida, M., Matsumori, A., Minato,. N. and Honjo, T. Nature Medicine 9 1477-1483 (2003)

PD-1 and PD-1 ligands: from discovery to clinical application. (Review) Okazaki, T. and Honjo, T. Int. Immunol. 19 813-824 (2007)

PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. Okazaki, T., Okazaki, I., Wang, J., Sugiura, D., Nakaki, F., Yoshida, T., Kato, Y., Fagarasan, S., Muramatsu, M., Eto, T., Hioki, K. and Honjo, T. J. Exp. Med. 208 395-407 (2011)

A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application.Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. and Honjo, T. Nat. Immunol. 14 1212–1218 (2013)