has today decided to award
the 2018 Nobel Prize in Physiology or Medicine
James P. Allison and Tasuku Honjo
for their discovery of cancer therapy by inhibition of negative immune regulation
Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the
inherent ability of our immune system to attack tumor cells this year’s Nobel Laureates have established an entirely new
principle for cancer therapy.
James P. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of
releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a
brand new approach for treating patients.
In parallel, Tasuku Honjo discovered a protein on immune cells and, after careful exploration of its function,
eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his
discovery proved to be strikingly effective in the fight against cancer.
Allison and Honjo showed how different strategies for inhibiting the brakes on the immune system can be used in the
treatment of cancer. The seminal discoveries by the two Laureates constitute a landmark in our fight against cancer.
Can our immune defense be engaged for cancer treatment?
Cancer comprises many different diseases, all characterized by uncontrolled proliferation of abnormal cells with
capacity for spread to healthy organs and tissues. A number of therapeutic approaches are available for cancer
treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes.
These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchins,
1988), and bone marrow transplantation for leukemia (Thomas 1990). However, advanced cancer remains immensely difficult
to treat, and novel therapeutic strategies are desperately needed.
In the late 19th century and beginning of the 20th century the concept emerged that activation of the immune system
might be a strategy for attacking tumor cells. Attempts were made to infect patients with bacteria to activate the
defense. These efforts only had modest effects, but a variant of this strategy is used today in the treatment of bladder
cancer. It was realized that more knowledge was needed. Many scientists engaged in intense basic research and uncovered
fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. Despite
remarkable scientific progress, attempts to develop generalizable new strategies against cancer proved difficult.
Accelerators and brakes in our immune system
The fundamental property of our immune system is the ability to discriminate “self” from “non-self” so that invading
bacteria, viruses and other dangers can be attacked and eliminated. T cells, a type of white blood cell, are key players
in this defense. T cells were shown to have receptors that bind to structures recognized as non-self and such
interactions trigger the immune system to engage in defense. But additional proteins acting as T-cell accelerators are
also required to trigger a full-blown immune response (see Figure). Many scientists contributed to this important basic
research and identified other proteins that function as brakes on the T cells, inhibiting immune activation. This
intricate balance between accelerators and brakes is essential for tight control. It ensures that the immune system is
sufficiently engaged in attack against foreign microorganisms while avoiding the excessive activation that can lead to
autoimmune destruction of healthy cells and tissues.
A new principle for immune therapy
During the 1990s, in his laboratory at the University of California, Berkeley, James P. Allison studied the T-cell
protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T
cells. Other research teams exploited the mechanism as a target in the treatment of autoimmune disease. Allison,
however, had an entirely different idea. He had already developed an antibody that could bind to CTLA-4 and block its
function (see Figure). He now set out to investigate if CTLA-4 blockade could disengage the T-cell brake and unleash the
immune system to attack cancer cells. Allison and co-workers performed a first experiment at the end of 1994, and in
their excitement it was immediately repeated over the Christmas break. The results were spectacular. Mice with cancer
had been cured by treatment with the antibodies that inhibit the brake and unlock antitumor T-cell activity. Despite
little interest from the pharmaceutical industry, Allison continued his intense efforts to develop the strategy into a
therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed
striking effects in patients with advanced melanoma, a type of skin cancer. In several patients signs of remaining
cancer disappeared. Such remarkable results had never been seen before in this patient group.
Figure: Upper left: Activation of T cells requires that the T-cell receptor binds to structures on other immune cells
recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA- 4
functions as a brake on T cells that inhibits the function of the accelerator. Lower left: Antibodies (green) against
CTLA-4 block the function of the brake leading to activation of T cells and attack on cancer cells.Upper right: PD-1 is
another T-cell brake that inhibits T-cell activation. Lower right: Antibodies against PD-1 inhibit the function of the
brake leading to activation of T cells and highly efficient attack on cancer cells.
Discovery of PD-1 and its importance for cancer therapy
In 1992, a few years before Allison’s discovery, Tasuku Honjo discovered PD-1, another protein expressed on the surface
of T-cells. Determined to unravel its role, he meticulously explored its function in a series of elegant experiments
performed over many years in his laboratory at Kyoto University. The results showed that PD-1, similar to CTLA-4,
functions as a T-cell brake, but operates by a different mechanism (see Figure). In animal experiments, PD-1 blockade
was also shown to be a promising strategy in the fight against cancer, as demonstrated by Honjo and other groups. This
paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a
key study demonstrated clear efficacy in the treatment of patients with different types of cancer. Results were
dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that
had previously been considered essentially untreatable.
Immune checkpoint therapy for cancer today and in the future
After the initial studies showing the effects of CTLA-4 and PD-1 blockade, the clinical development has been dramatic.
We now know that the treatment, often referred to as “immune checkpoint therapy”, has fundamentally changed the outcome
for certain groups of patients with advanced cancer. Similar to other cancer therapies, adverse side effects are seen,
which can be serious and even life threatening. They are caused by an overactive immune response leading to autoimmune
reactions, but are usually manageable. Intense continuing research is focused on elucidating mechanisms of action, with
the aim of improving therapies and reducing side effects.
Of the two treatment strategies, checkpoint therapy against PD-1 has proven more effective and positive results are
being observed in several types of cancer, including lung cancer, renal cancer, lymphoma and melanoma. New clinical
studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated
in patients with melanoma. Thus, Allison and Honjo have inspired efforts to combine different strategies to release the
brakes on the immune system with the aim of eliminating tumor cells even more efficiently. A large number of checkpoint
therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as
For more than 100 years scientists attempted to engage the immune system in the fight against cancer. Until the seminal
discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now
revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.
Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed
cell death. EMBO J., 11(11), 3887–3895.
Leach, D. R., Krummel, M. F., & Allison, J. P. (1996). Enhancement of antitumor immunity by CTLA-4 blockade. Science, 271(5256), 1734–1736.
Kwon, E. D., Hurwitz, A. A., Foster, B. A., Madias, C., Feldhaus, A. L., Greenberg, N. M., Burg, M.B. & Allison, J.P. (1997). Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci USA, 94(15), 8099–8103.
Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T. (1999). Development of Lupus-like Autoimmune Diseases by Disruption of the PD-1 gene encoding an ITIM
motif-carrying immunoreceptor. Immunity, 11, 141–151.
Freeman, G.J., Long, A.J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, 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. & Honjo, T. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative
regulation of lymphocyte activation. J Exp Med, 192(7), 1027–1034.
Hodi, F.S., Mihm, M.C., Soiffer, R.J., Haluska, F.G., Butler, M., Seiden, M.V., Davis, T., Henry-Spires, R., MacRae, S.,
Willman, A., Padera, R., Jaklitsch, M.T., Shankar, S., Chen, T.C., Korman, A., Allison, J.P. & Dranoff, G. (2003). Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously
vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA, 100(8), 4712-4717.
Iwai, Y., Terawaki, S., & Honjo, T. (2005). PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment
of effector T cells. Int Immunol, 17(2), 133–144.
James P. Allison was born 1948 in Alice, Texas, USA. He received his PhD in 1973 at the University of Texas, Austin. From 1974-1977 he
was a postdoctoral fellow at the Scripps Clinic and Research Foundation, La Jolla, California. From 1977-1984 he was a
faculty member at University of Texas System Cancer Center, Smithville, Texas; from 1985-2004 at University of
California, Berkeley and from 2004-2012 at Memorial Sloan-Kettering Cancer Center, New York. From 1997-2012 he was an
Investigator at the Howard Hughes Medical Institute. Since 2012 he has been Professor at University of Texas MD Anderson
Cancer Center, Houston, Texas and is affiliated with the Parker Institute for Cancer Immunotherapy.
Tasuku Honjo was born in 1942 in Kyoto, Japan. In 1966 he became an MD, and from 1971-1974 he was a research fellow in USA at
Carnegie Institution of Washington, Baltimore and at the National Institutes of Health, Bethesda, Maryland. He received
his PhD in 1975 at Kyoto University. From 1974-1979 he was a faculty member at Tokyo University and from 1979-1984 at
Osaka University. Since 1984 he has been Professor at Kyoto University. He was a Faculty Dean from 1996-2000 and from
2002-2004 at Kyoto University.
Illustrations: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén
The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or
Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who
have made the most important discoveries for the benefit of humankind.
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