What will be known in 2018
Who received the Nobel Prize in Physiology or Medicine in 2018 and for what?
The Nobel Prize in Physiology or Medicine focuses on research into cancer immunotherapies. Two pioneers in the field were recognized for their almost lifelong research in the field.
James P. Allison
The scientists, born in 1948, worked at several renowned and large cancer research institutes. His career has seen stints at Berkely, Scripps and MD Anderson Cancer Research Centers, in his Texan homeland.
The Japanese scientist was born in 1942. His career stations include research institutions in the USA and Japan. He worked at the NIH, the Carnegie Institution and universities in Tokyo, Osaka and Kyoto, his birthplace.
Cancer kills millions of people every year and is one of the greatest health challenges facing humanity. By stimulating the inherent ability of our immune system to attack tumor cells, this year's Nobel Prize winners have established a completely new principle for cancer therapy.
James P. Allison studied a well-known protein that acts as a brake on the immune system. He recognized the potential to release the brakes and thus free our immune cells to attack tumors. He then developed this concept into a completely new approach to treating patients.
At the same time, Tasuku Honjo discovered a protein on immune cells and, after carefully researching its function, finally showed that it also works as a brake, but with a different mechanism of action. The therapies based on his discovery have been shown to be remarkably effective in the fight against cancer.
Allison and Honjo showed how various strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer. The groundbreaking discoveries made by the two award winners are a milestone in our fight against cancer.
Can our immune defenses be used for cancer treatment?
Cancer encompasses a wide variety of diseases, all of which are characterized by the uncontrolled reproduction of abnormal cells with the ability to spread to healthy organs and tissues. A number of therapeutic approaches are available to cancer treatment, including surgery, radiation, and other strategies, some of which have won previous Nobel Prizes. These include methods of hormone treatment for prostate cancer, chemotherapy, and bone marrow transplantation for leukemia. However, advanced cancer treatment remains immensely difficult and new therapeutic strategies are urgently needed.
In the late 19th and early 20th centuries, the concept arose that activating the immune system could be a strategy for attacking tumor cells. Attempts have been made to infect patients with bacteria in order to activate the immune system. These efforts had little effect, but a variant of this strategy is now used in the treatment of bladder cancer. It was found that more knowledge was needed. Many scientists conduct intensive basic research and discovered basic mechanisms that regulate immunity and also showed how the immune system can recognize cancer cells. Despite remarkable scientific advances, trying to develop generalizable new strategies against cancer has proven difficult.
Accelerators and brakes in our immune system
The fundamental property of our immune system is the ability to distinguish "self" from "not-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. It has been shown that T cells have receptors that bind to structures that are not recognized as self, and such interactions trigger the immune system to engage in defense. But additional proteins that act as T-cell accelerators are also required to trigger a complete immune response. Many scientists contributed to this important basic research and identified other proteins that act as brakes on T cells and inhibit immune activation. This intricate balance between accelerator pedals and brakes is essential for tight control. It ensures that the immune system takes adequate action against foreign microorganisms and at the same time avoids the excessive activation that can lead to the destruction of healthy cells and tissues by autoimmune diseases.
A new concept for immunotherapy
In the 1990s, James P. Allison studied the T-cell protein CTLA-4 in his laboratory at the University of California, Berkeley. He was one of several scientists who had observed that CTLA-4 acts as a brake on T cells. Other research teams have used the mechanism as a target in the treatment of autoimmune diseases. However, Allison had a very different idea. He had already developed an antibody that could bind to CTLA-4 and block its function. He now set out to investigate whether the CTLA-4 blockade could release the T-cell brake and activate the immune system to attack cancer cells. Allison and his team carried out a first experiment at the end of 1994, which, in their enthusiasm, was repeated immediately during the Christmas break. The results were spectacular. Mice with cancer were cured by treatment with the antibodies that inhibit the brake and release anti-tumor T cell activity. Despite little interest from the pharmaceutical industry, Allison continued his intensive 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. The signs of residual cancer disappeared in several patients. Such remarkable results had never been seen before in this patient population.
Discovery of PD-1 and its importance in cancer therapy
In 1992, a few years before Allison's discovery, Tasuku Honjo discovered PD-1, another protein that is expressed on the surface of T cells. Determined to untangle his role, he meticulously examined its function in a series of elegant experiments that he carried out over many years in his laboratory at Kyoto University. The results showed that PD-1, similar to CTLA-4, works as a T-cell brake, but works with a different mechanism. In animal studies, the PD-1 blockade also proved to be a promising strategy in the fight against cancer, as Honjo and other groups show. Clinical development followed, and in 2012 a key study showed clear efficacy in treating patients with various types of cancer. The results have been dramatic, resulting in long-term remission and possible cure in several patients with metastatic cancer, a condition previously thought to be essentially untreatable.
Immune checkpoint therapy for cancer today and in the future
After the first studies showing the effects of CTLA-4 and PD-1 blockade, clinical development has been dramatic. We now know that treatment, often referred to as "immune checkpoint therapy", has profoundly changed outcomes for certain groups of patients with advanced cancer. Similar to other cancer therapies, there are unwanted side effects that can be serious and even life-threatening. They are caused by an overactive immune response that leads to autoimmune reactions, but are usually manageable. The intensive further work focuses on the elucidation of mechanisms of action with the aim of improving the therapy and reducing side effects.
Of the two treatment strategies, checkpoint therapy against PD-1 has been shown to be more effective, and positive results are seen in a variety of cancers, including lung cancer, kidney cancer, lymphoma, and melanoma. New clinical studies show that combination therapy targeting both CTLA-4 and PD-1 can be even more effective, as shown in patients with melanoma. Allison and Honjo have made efforts to combine different strategies in order to release the brakes on the immune system and to eliminate tumor cells even more efficiently. A large number of checkpoint therapy trials are currently ongoing for most cancers, and new checkpoint proteins are being tested as targets.
For more than 100 years, scientists have tried to involve the immune system in the fight against cancer. Until the groundbreaking discoveries of the two award winners, the progress in clinical development was modest: Checkpoint therapy revolutionized cancer treatment and fundamentally changed the way we treat cancer.
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