Nobel Prize in Physiology or Medicine 2018: Cancer Therapy by Releasing Immune Brakes

This note covers the Nobel Prize in Physiology or Medicine 2018: who won it, how James P. Allison and Tasuku Honjo discovered that releasing the "brakes" on immune T cells can make the immune system attack cancer, how checkpoint therapy developed from basic research into approved treatments, why it matters, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2018 awarded for?

The official citation reads: "for their discovery of cancer therapy by inhibition of negative immune regulation". This is the full wording used by the prize-giving body, officially called the Nobel Prize in Physiology or Medicine.

In plain language, the two laureates found that our immune system has built-in "brakes" that normally stop immune cells from attacking the body's own tissues too fiercely. Cancer cells can hide behind these brakes.

Allison and Tasuku Honjo separately found two different brake proteins on T cells (a type of white blood cell) and showed that blocking each brake with an antibody could unleash the immune system to attack tumours.

This idea became the basis of a new class of cancer drugs, now called checkpoint inhibitors.

This prize is decided by the Nobel Assembly at Karolinska Institutet, whose Nobel Committee evaluates the nominations each year.

Who are the laureates?

James P. Allison

James P. Allison was born on 7 August 1948 in Alice, TX, USA. At the time of the award he was affiliated with the Parker Institute for Cancer Immunotherapy, San Francisco, and the University of Texas MD Anderson Cancer Center, Houston. He received one half of the prize.

Allison studied a protein called CTLA-4, which acts as a brake on T cells. Working at the University of California, Berkeley, in the 1990s, he developed an antibody that could block CTLA-4 and tested it in mice with cancer at the end of 1994.

The results were, in the words of the press release, described as the mice being cured of their tumours.

He then pushed the idea through years of further animal studies and clinical development into a treatment for human patients, despite initial lack of interest from the pharmaceutical industry.

Tasuku Honjo

Tasuku Honjo was born on 27 January 1942 in Kyoto, Japan. At the time of the award he was affiliated with Kyoto University, Kyoto, Japan. He also received one half of the prize.

In 1992, working in his own laboratory at Kyoto University, Honjo discovered a different T-cell surface protein, PD-1.

Through years of careful experiments he showed that PD-1, like CTLA-4, also works as a brake on T cells, but through a different biological mechanism.

Antibodies blocking PD-1 later proved, according to the press release, strikingly effective against cancer in clinical trials.

What problem were Allison and Honjo trying to solve?

Cancer is not one disease but a group of diseases in which abnormal cells divide without control and spread into healthy tissue and, eventually, to distant organs as metastases.

The scientific background document notes that cancer was estimated to be diagnosed in more than 18 million people worldwide in 2018, and that global cancer deaths that year were estimated to surpass 9 million.

By the time of this prize, three established pillars of cancer treatment existed: surgery, radiotherapy and drugs that attack the cancer cells directly (such as chemotherapy).

Each had already earned earlier Nobel recognition, for example hormone treatment for prostate cancer (Huggins, 1966), chemotherapy principles (Elion and Hitchings, 1988) and bone marrow transplantation (Thomas, 1990).

Even so, advanced and metastatic cancer remained very hard to treat, and the press release said that novel therapeutic strategies were "desperately needed".

The idea of using the immune system against cancer is old. In the late 19th century, doctors such as William B. Coley tried infecting cancer patients with bacteria to stimulate an immune reaction, with only modest and inconsistent results; a related approach is still used today for bladder cancer.

Across the 20th century scientists built up deep knowledge of how the immune system distinguishes the body's own cells ("self") from foreign invaders ("non-self") using T cells and their receptors, yet translating this basic knowledge into a working cancer therapy proved extremely difficult for over a hundred years.

How do the "accelerator and brake" system of T cells work?

T cells use a receptor to recognise structures that look foreign. But recognition alone is not enough: the press release explains that T cells also need a second signal, from proteins acting as accelerators, to mount a full immune attack.

Just as important, other proteins act as brakes that inhibit this activation.

This balance between accelerators and brakes is essential. If the brakes are too weak, the immune system can attack the body's own healthy tissues, causing autoimmune disease.

If the brakes are too strong, or if a tumour exploits them, the immune system fails to attack cancer cells even when it has already recognised them as abnormal.

Draw a T cell with its receptor binding to a foreign-looking structure on another immune cell. Add a second protein shown as an "accelerator" switch feeding into the T cell.

Beside it draw a brake-shaped protein (label it CTLA-4 or PD-1) blocking the activation signal, then show an antibody molecule attaching to the brake protein and switching it off, with an arrow showing the T cell now attacking a cancer cell.

The basic steps by which scientists worked out this mechanism, as described in the scientific background, were as follows:

1. Researchers identified the T-cell receptor and showed it needed to bind structures recognised as non-self to trigger a response.
2. They found that receptor binding alone was insufficient, leading to the discovery of costimulatory "accelerator" proteins such as CD28.
3. Further work identified related proteins, including CTLA-4 and later PD-1, that instead inhibit T-cell activation and act as brakes.
4. Scientists created antibodies against these brake proteins and tested whether blocking them could release a stronger immune attack, first in mice and then in patients.

How did Allison's CTLA-4 approach become cancer therapy?

Allison realised that blocking the CTLA-4 brake, rather than just studying it, could unleash T cells against tumours.

According to the press release, Allison's team ran their first test at the end of 1994 and, excited by the result, repeated it right away over the Christmas break: mice with cancer went into remission after treatment with the CTLA-4-blocking antibodies.

Despite little early interest from pharmaceutical companies, Allison pursued the idea further. Promising animal results in other cancer types followed, and in 2010 an important clinical study reported striking effects in patients with advanced melanoma (a type of skin cancer), with the press release noting that in several patients the remaining cancer disappeared, an outcome that, in the press release's words, "had never been seen before in this patient group".

In parallel, Honjo's PD-1 discovery followed a similar arc: careful laboratory study of the protein's function, animal experiments showing blockade could fight cancer, and then clinical trials.

A key 2012 clinical study, according to the press release, demonstrated clear efficacy in treating patients with different cancer types, with some patients with metastatic cancer, previously considered essentially untreatable, achieving long-term remission.

How did the discovery unfold?

This timeline shows that the two discoveries, though united by this one prize, began years apart and followed largely separate paths before converging into the shared idea of checkpoint therapy.

Honjo's PD-1 work started from a search into cell death rather than cancer, while Allison's CTLA-4 breakthrough grew out of long-running basic research into how T cells are switched on and off.

It took roughly a century, from the first attempts to use infections against tumours in the late 1800s, before this basic immunology knowledge turned into reliable, approved cancer treatments.

Why does immune checkpoint therapy matter?

The press release calls this discovery a "landmark in our fight against cancer". Treatments based on blocking CTLA-4 and PD-1, now widely known as immune checkpoint therapy, have changed outcomes for some patients with advanced cancers, including melanoma, lung cancer, renal cancer and lymphoma, according to the sources.

The sources also note that combining anti-CTLA-4 and anti-PD-1 treatment can be even more effective than either alone, as shown in melanoma patients, inspiring further combination research.

However, the treatment is not without cost: because it works by releasing the immune system's own brakes, it can also cause the immune system to attack the body's own healthy tissue, leading to autoimmune side effects that are described as sometimes serious and even life threatening, though usually manageable.

Open questions mentioned in the sources include why only some patients respond, how to predict response in advance, and how to reduce side effects, with continuing research into the biological mechanisms and new checkpoint proteins as additional targets.

How does this connect to what you study?

This discovery links directly to school biology topics on the immune system, where T cells and antibodies are usually introduced as defenders against infection rather than as tools against cancer.

This prize shows the same cells and molecules, redirected against tumours, illustrating how basic immunology research, not originally aimed at cancer at all, can lead to real medical treatments years later. Honjo, for example, was initially investigating programmed cell death when he found PD-1, not studying cancer directly.

It also connects to lessons on cell biology, since cancer itself is explained as the result of uncontrolled cell division and migration into healthy tissue, a concept usually covered when studying the cell cycle and tumours.

Students studying antibodies and how they recognise specific target molecules can see a direct real-world application here: the checkpoint inhibitor drugs described in this note are themselves antibodies engineered to bind tightly to one target protein, CTLA-4 or PD-1, and block its function.

The idea of a biological "brake" and "accelerator" system, kept in balance so the body neither under-reacts to danger nor attacks itself, is also a useful model for thinking about feedback and regulation more generally in the biological sciences.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2018 was awarded jointly to James P. Allison and Tasuku Honjo for discovering cancer therapy by inhibiting negative immune regulation, that is, blocking brake proteins on T cells so the immune system attacks tumours.

The prize was announced on 1 October 2018 by the Nobel Assembly at Karolinska Institutet, whose Nobel Committee evaluates the nominations.

Allison, born in Alice, Texas, USA, worked at the Parker Institute for Cancer Immunotherapy and the University of Texas MD Anderson Cancer Center. Honjo, born in Kyoto, Japan, worked at Kyoto University.

Each laureate received one half of the prize, worth 9,000,000 Swedish kronor in total that year.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• T cell — a type of white blood cell that can recognise and attack cells seen as foreign or abnormal.
• CTLA-4 — a brake protein on T cells studied by James P. Allison, which normally inhibits T-cell activation.
• PD-1 — a brake protein on T cells discovered by Tasuku Honjo in 1992, which inhibits T-cell activation by a different mechanism than CTLA-4.
• Immune checkpoint — a brake mechanism in the immune system that normally prevents excessive or self-damaging immune responses.
• Checkpoint inhibitor — a drug, usually an antibody, that blocks a checkpoint brake protein so the immune system becomes more active against a tumour.
• Metastasis — the spread of cancer cells from their original site to other organs via blood or lymph vessels.
• Autoimmune disease — a condition where the immune system mistakenly attacks the body's own healthy tissues.
• Antibody — a protein made by the immune system (or produced in a laboratory) that binds tightly to a specific target molecule.
• Melanoma — a type of skin cancer, used as an important test case for early checkpoint-inhibitor trials.
• Negative immune regulation — the general process by which brake proteins hold back or limit immune responses.
• Clinical trial — a structured study testing a treatment's safety and effectiveness in human patients.

Common errors and misconceptions

• Misconception: Checkpoint therapy directly kills cancer cells like chemotherapy. Correct: It works by releasing brakes on the patient's own T cells, which then attack the tumour.
• Misconception: Allison and Honjo worked together as a team. Correct: They worked independently, Allison in the USA and Honjo in Japan, and discovered two different brake proteins by separate research paths.
• Misconception: CTLA-4 and PD-1 work by the same mechanism. Correct: The press release states PD-1 also operates as a brake but "with a different mechanism of action" from CTLA-4.
• Misconception: Checkpoint therapy cures all cancer patients. Correct: The sources describe striking results in some patients and cancer types, but note that many patients do not respond and side effects can be serious.
• Misconception: This was the first attempt ever to use the immune system against cancer. Correct: Attempts to use infections to stimulate immunity against tumours date back to the late 19th century, though with limited success until this discovery.
• Misconception: The Nobel Prize in Physiology or Medicine is awarded by a committee in Oslo. Correct: It is awarded by the Nobel Assembly at Karolinska Institutet in Sweden.

Exam-style questions with model answers

Q1. State the official citation for the Nobel Prize in Physiology or Medicine 2018. [2 marks]

1. The citation reads "for their discovery of cancer therapy by inhibition of negative immune regulation", awarded jointly to James P. Allison and Tasuku Honjo.

Q2. Name the two brake proteins central to this discovery and who discovered each. [2 marks]

1. CTLA-4, studied by James P. Allison, and PD-1, discovered by Tasuku Honjo in 1992.

Q3. Explain in your own words why T cells need both "accelerators" and "brakes". [4 marks]

1. T cells use a receptor to detect structures that look foreign, but recognition alone does not fully activate them; a second signal from accelerator proteins is also needed to trigger a full immune response. Brake proteins such as CTLA-4 and PD-1 counterbalance this activation, preventing the immune system from becoming too aggressive. This balance stops the immune system from damaging the body's own healthy tissues through excessive activation, while still allowing it to fight off infections and, as this discovery showed, cancer cells once the brakes are released.

Q4. Describe how James P. Allison's early experiments with CTLA-4 blockade proceeded. [4 marks]

1. Allison studied CTLA-4 as a known brake protein on T cells and developed an antibody able to block its function. At the end of 1994, his laboratory tested this antibody in mice that had been given tumours, repeating the experiment over the Christmas break because of excitement about the results. The mice with cancer were cured by this antibody treatment, showing that releasing the CTLA-4 brake could unlock T cells to attack tumours, even though pharmaceutical companies initially showed little interest in developing it further.

Q5. Discuss why this discovery is considered a landmark in cancer treatment, including its benefits and limitations as stated in the sources. [6 marks]

1. Before this discovery, cancer treatment relied mainly on three pillars: surgery, radiotherapy and drugs attacking cancer cells directly, yet advanced cancer remained very hard to treat. Allison and Honjo showed that activating a patient's own immune system, by blocking the CTLA-4 and PD-1 brake proteins on T cells, could make the immune system attack tumours that it had previously failed to clear. Clinical trials reported striking results: in melanoma patients treated with anti-CTLA-4 antibodies, some showed disappearing tumours that had never been seen before in that patient group, and PD-1 blockade produced long-term remission in patients with metastatic cancer previously considered essentially untreatable. Combining both approaches can be even more effective than either alone. However, the sources also note limitations: because the treatment works by loosening immune brakes, it can cause the immune system to attack healthy tissue, leading to autoimmune side effects that are sometimes serious. Not all patients respond, and ongoing research continues into predicting who will benefit and how to reduce the side effects, meaning the discovery opened a promising new field rather than a complete cure.

Q6. When was the award announced, and by which body? [2 marks]

1. The award was announced on 1 October 2018 by the Nobel Assembly at Karolinska Institutet.

Q7. What is an immune checkpoint inhibitor? [3 marks]

1. An immune checkpoint inhibitor is a drug, usually an antibody, that blocks a brake protein such as CTLA-4 or PD-1 on T cells. By blocking the brake, it releases the T cells from inhibition, allowing them to mount a stronger attack against cancer cells, which is the therapeutic principle established by Allison and Honjo.

Key takeaways

• Allison and Honjo won the 2018 medicine prize for discovering how to treat cancer by blocking immune "brake" proteins.
• Allison studied CTLA-4; Honjo discovered PD-1 in 1992; each works as a brake by a different mechanism.
• Blocking these brakes with antibodies unleashes T cells to attack tumour cells, a strategy called checkpoint therapy.
• Allison's first successful mouse experiment took place at the end of 1994, confirmed over the Christmas break.
• Clinical trials from 2010 and 2012 showed striking benefits in melanoma and other advanced cancers.
• Combining anti-CTLA-4 and anti-PD-1 treatment can work better than either drug alone.
• The treatment can cause serious autoimmune side effects because it loosens the immune system's natural controls.
• The prize was announced on 1 October 2018 by the Nobel Assembly at Karolinska Institutet.

Test yourself

Who shared the 2018 Nobel Prize in Physiology or Medicine?

James P. Allison and Tasuku Honjo shared the prize equally for discovering cancer therapy through inhibition of negative immune regulation.

Where was James P. Allison working at the time of the award?

James P. Allison was affiliated with the Parker Institute for Cancer Immunotherapy and the University of Texas MD Anderson Cancer Center, both in the USA.

Where was Tasuku Honjo working at the time of the award?

Tasuku Honjo was affiliated with Kyoto University in Kyoto, Japan, at the time of the award.

What protein did Honjo discover in 1992?

Honjo discovered PD-1, a protein on immune cells that later proved to act as a brake on T-cell activation.

What is the basic idea behind checkpoint therapy?

Checkpoint therapy blocks brake proteins on T cells, such as CTLA-4 or PD-1, so the immune system can attack cancer cells more strongly.

Name one cancer type where checkpoint therapy showed early strong results.

Advanced melanoma, a type of skin cancer, showed striking results in early clinical trials of CTLA-4 blockade.

What side effect risk is linked to checkpoint therapy?

Because it releases immune brakes, checkpoint therapy can cause autoimmune reactions that are sometimes serious or life threatening.