2018 Nobel Prize in Physiology or Medicine: Allison and Honjo Unlock the Brakes on the Immune System to Fight Cancer

What You Will Learn in This Article

The 2018 Nobel Prize in Physiology or Medicine was awarded to two individuals who elucidated the regulatory brakes of the immune system, ushering in a new era of cancer immunotherapy. James Allison of MD Anderson Cancer Center at the University of Texas, revealed that CTLA-4 on T cells acts as a brake that suppresses excessive T cell activity. He demonstrated, in mice and humans, that blocking this brake with an antibody enables the immune system to attack tumors. Tasuku Honjo of Kyoto University, Japan, discovered a separate brake called PD-1 and showed that antibodies targeting it have remarkable effects on various advanced cancers. The immunotherapies developed based on these two discoveries, including ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), have become standard treatments for over 20 types of cancers, such as melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, liver cancer, and head and neck cancer. This represents a pivotal turning point in 21st-century cancer treatment.

A Counterintuitive Concept: Tumors Use the Immune System's Brakes to Escape

The common belief that "cancer originates from the body's own cells, so the immune system doesn't recognize it" is only partially true. In reality, our body's T cells can recognize a significant number of mutated antigens on tumor cells. However, the reason most tumors survive is that they exploit the immune system's natural brakes to neutralize T cell attacks.

CTLA-4 and PD-1 are natural brakes designed to prevent T cell responses from becoming excessively strong. After an infection is cleared, if T cells continue to be activated, autoimmune reactions can occur. Therefore, the body uses these brakes to regulate the immune response. However, tumors subvert this system. Tumor cells and the surrounding tissues express PD-L1 (the ligand for PD-1), sending a "do not attack" signal to T cells. The T cells, with their brakes engaged, pass by the tumor, allowing it to continue to grow.

In terms of a Control Systems (CS) framework, this is a scenario where an adversary exploits a kill switch in a normal system. The kill switch, originally designed as a safety mechanism to maintain system stability, is activated by the attacker, disabling the response process. Immunotherapies reverse this situation. By physically blocking CTLA-4 or PD-1 with antibodies, the brakes on T cells are released, allowing them to attack tumor cells. Under the premise that tumor-specific T cells already exist in the body, immunotherapies liberate these T cells by preventing them from being inhibited.

The Zeitgeist: The Panmunjom Bridge and the Singapore Summit

In 2018, South Korea experienced a dramatic shift in its inter-Korean relations. The Pyeongchang Winter Olympics, held from February 9 to 25, featured a joint opening ceremony with North Korea, and the Korean flag was displayed in the stadium. This symbolic moment led to a summit between the two Koreas. On April 27, South Korean President Moon Jae-in met with North Korean leader Kim Jong-un at the Panmunjom and issued the Panmunjom Declaration. The scene of the two leaders engaging in personal conversation on the bridge became a symbolic image that resonated around the world, marking the beginning of a new phase in the Korean peace process.

On June 12, the first-ever U.S.-North Korea summit was held in Singapore between President Trump and Kim Jong-un. While it was considered more symbolic than substantive, it undoubtedly created a new variable in international politics. This momentum faced several ups and downs in the following years.

Domestically, the debate surrounding the substantial increase in the minimum wage intensified, and the #MeToo movement spread throughout South Korea, leading to revelations of sexual misconduct involving prominent figures in the cultural and political spheres.

Globally, in November, He Jiankui of China announced the birth of genetically edited twin babies using CRISPR, sparking widespread international condemnation. This was the first case of applying gene editing in embryos for clinical purposes, and it highlighted the urgent need for strong international consensus on the regulation of biotechnology. He Jiankui was subsequently found guilty by a Chinese court.

In the scientific community, this prize was a recognition of the generational shift in cancer treatment. Over the past 100 years, cancer treatment has evolved from cytotoxic chemotherapy, which kills cancer cells directly, to targeted small molecules and then to targeted antibodies. However, the approach of activating the immune system itself had a long history of failure. Allison and Honjo broke through this barrier, and the Nobel Committee awarded the prize to these two pioneers of this breakthrough.

Personal Narratives: A Rock Musician from Texas and a Quiet Scholar from Kyoto

James Allison (1948-) was born in Alice, Texas. He received his bachelor's and doctoral degrees from the University of Texas at Austin and subsequently worked at the University of California, Berkeley, Memorial Sloan Kettering Cancer Center, and MD Anderson Cancer Center at the University of Texas. In addition to his academic career, he is also known as a rock harmonica musician. It is said that he performed with his band, "The Checkmates," in Stockholm the day before the Nobel Prize ceremony.

Allison's approach to the problem was bold. In the early 1990s, research on T cell activation pathways revealed that CD28 is a co-stimulatory receptor that activates T cells. However, the function of another receptor with a similar structure, CTLA-4—which is only expressed on activated T cells—remained a mystery. Most researchers assumed that CTLA-4 was a co-stimulatory receptor that assisted CD28. However, Allison proposed a counter-hypothesis: "Could CTLA-4 actually be a brake that inhibits T cells?"

In 1996, Allison's team published a paper that proved this hypothesis. Blocking this receptor with an anti-CTLA-4 antibody enhanced the ability of mouse T cells to attack tumors, and established tumors regressed. This observation was the first empirical evidence of the concept of immune checkpoint inhibitors. Subsequent clinical development led to the approval of ipilimumab (brand name Yervoy) by the U.S. FDA in 2011 as a treatment for advanced melanoma. This was the first drug in over 20 years to show a significant improvement in survival in advanced melanoma.

Tasuku Honjo (1942-) was born in Kyoto, Japan. He received his M.D. from Kyoto University and his Ph.D. from the University of Tokyo. After completing his postdoctoral research at the Carnegie Institution of Washington and the National Institutes of Health, he established his own laboratory at Osaka University and Kyoto University, where he spent his entire career. His early and significant work was the elucidation of the molecular mechanism of immunoglobulin class switching—the genetic recombination that changes the class of antibodies from IgM to IgG and IgE. He discovered the key enzyme, AID (activation-induced cytidine deaminase), and established a major pillar in this field.

PD-1 was discovered serendipitously in Honjo's laboratory in 1992. While searching for genes related to apoptosis, he cloned a gene that he named "Programmed cell Death-1." Although the name initially did not reflect its actual function, it stuck. His laboratory later revealed that PD-1 is an inhibitory receptor on T cells and contributes to the prevention of autoimmune diseases.

Allison and Honjo independently discovered their respective brakes, and the two approaches converged in clinical practice. Anti-PD-1 antibodies—nivolumab (Opdivo, 2014) and pembrolizumab (Keytruda, 2014)—showed remarkable response rates in various advanced cancers and became the new standard of care for 21st-century cancer treatment. In particular, pembrolizumab (Keytruda) has obtained approval for over 20 cancer indications and has become the world's best-selling cancer drug.

The two men had contrasting styles. Allison was outgoing and enjoyed media exposure, while Honjo was quiet and scholarly. The scene of the two men standing side by side at the award ceremony became a symbolic image of 21st-century cancer immunotherapy.

Key Achievements: The Architecture of Immune Checkpoint Inhibition in a CS Framework

The normal pipeline of T cell activation can be depicted as follows:

• Activation Signal 1: Antigen-presenting cells (APCs) present antigen fragments on their surface MHC molecules to T cells. When the T cell receptor (TCR) on the T cell specifically recognizes this antigen, an activation signal is generated.
• Activation Signal 2 (Co-stimulation): CD28 on the T cell surface binds to B7 (CD80/86) on the APC surface, completing the activation. Both of these signals must be present for the T cell to be fully activated.
• Natural Brake (CTLA-4): A few hours to days after T cell activation, CTLA-4 appears on the surface. CTLA-4 binds to B7 much more strongly than CD28, inhibiting the activation signal from CD28. This is a natural kill switch to prevent T cell responses from becoming unlimited.
• Peripheral Inhibition (PD-1/PD-L1): Activated T cells also express PD-1. When target tissues express PD-L1, T cell attack is inhibited. This is a peripheral tolerance mechanism that prevents accidental attacks on self-tissues.

The tumor's evasion architecture manipulates this normal system.

• CTLA-4 Axis: Tumors induce the expression of CTLA-4 on T cells, inhibiting their initial activation. This is why T cells in the vicinity of the tumor are not fully activated.
• PD-1/PD-L1 Axis: Tumor cells and various cells in the tumor microenvironment (such as macrophages and fibroblasts) express large amounts of PD-L1, sending a continuous "do not attack" signal to T cells. Even if T cells are activated, they are neutralized when they reach the tumor.

The action of immune checkpoint inhibitors reverses this evasion system.

• Anti-CTLA-4 (Ipilimumab): Binds to CTLA-4, physically blocking this brake. This restores initial T cell activation.
• Anti-PD-1 (Nivolumab, Pembrolizumab): Binds to PD-1, neutralizing the PD-L1 signal from the tumor. This allows activated T cells to attack the tumor.
• Anti-PD-L1 (Atezolizumab, Avelumab, etc.): Binds to PD-L1, achieving the same result.
• Combination Therapy: In some cancers, such as melanoma, blocking both CTLA-4 and PD-1 simultaneously results in greater efficacy. However, side effects are also increased.

The CS analogy for this system is clear: It is a scenario where an adversary exploits a kill switch in a normal system, and antibodies physically lock that kill switch. This architecture is remarkably similar to the response framework in software security. If a vulnerability is found where a normal defense process is killed by a specific signal, a firewall rule is added to neutralize that kill signal.

However, the limitations of this analogy should also be acknowledged. Immune checkpoint inhibitors do not create T cell specificity themselves. Tumor-specific T cells must already exist in the body for immune checkpoint inhibition to be meaningful. Tumors with high immunogenicity—tumors with many mutations that T cells can already recognize—are more responsive. In "cold" tumors with low immunogenicity, the response rate is lower. This heterogeneity in response rate is one of the major challenges in current immunotherapy development, and various combination therapies are being developed.

Why It Matters: Between the 20th and 21st Centuries in Cancer Treatment

First, the redefinition of advanced melanoma. Before the approval of ipilimumab, advanced melanoma had a dismal prognosis with a 5-year survival rate of less than 5%. After ipilimumab, and especially after the combination therapy with PD-1 inhibitors, a patient population with a 5-year survival rate exceeding 50% emerged. This fundamental shift in prognosis is one of the most remarkable events in the last 100 years of cancer treatment history. Melanoma, once on the list of treatment failures in the late 20th century, has been completely transformed into a success story in the 21st century.

Second, a change in the standard treatment for several advanced cancers. In non-small cell lung cancer, PD-1 inhibitors have become first-line treatments, demonstrating significant survival improvements compared to chemotherapy alone. Checkpoint inhibitors have been approved for over 20 types of cancer, including kidney cancer, bladder cancer, head and neck cancer, hepatocellular carcinoma, and endometrial cancer, and the standard treatment for each type of cancer has been reorganized.

Third, the widespread adoption of biomarker-based precision medicine. The PD-L1 expression test is now quantified in tumor tissue and used to predict the response rate to checkpoint inhibitors. The observation that tumors with a high tumor mutational burden (TMB) have higher response rates has also been established, and these markers are now used in clinical decision-making. Regardless of the cancer type, a new approval category called tissue-agnostic approval has been created for cases with high TMB or microsatellite instability (MSI-H).

Fourth, the era of combination therapy. Various combinations are being developed to treat patients who do not respond to checkpoint inhibitors alone. These include checkpoint inhibitors + chemotherapy, checkpoint inhibitors + targeted antibodies, checkpoint inhibitors + radiation, and checkpoint inhibitors + other immune activators. Most of today's clinical trials for advanced cancers include checkpoint inhibitors in some form.

Fifth, new clinical management of immune-related adverse events is needed. Checkpoint inhibitors broadly enhance T-cell responses, which can lead to autoimmune-like adverse events – such as dermatitis, colitis, hepatitis, and endocrine disorders. Early detection and management of these adverse events have become the new standard of care in clinical oncology.

Sixth, the expansion of immunotherapy. Following the success of checkpoint inhibitors, various other immunotherapeutic approaches have been activated. These include CAR-T cell therapy (genetically modifying patient T cells to target tumors), cancer vaccines (inducing an immune response against specific tumor antigens), oncolytic viruses (viruses that specifically infect and kill tumors), and bispecific antibodies (simultaneously binding T cells and tumor cells to bring them into contact). All of these approaches can be combined with checkpoint inhibitors, and cancer treatment in the latter half of the 21st century will focus on how to combine these tools.

Seventh, a reorganization of our understanding of the human immune system. One answer to the question of why our bodies don't completely eliminate tumors emerged from this story. The immune system does not completely ignore tumors, but tumors exploit the system's regulatory circuits and make it impossible to win. This perspective has been applied to other immune issues, such as autoimmune diseases, infectious diseases, and graft rejection, and a new treatment principle called fine-tuning immune responses through checkpoint manipulation is being developed in several areas.

T cells were already recognizing the tumor, but they were unable to attack because of the brakes. This insight revolutionized cancer treatment in the early 21st century. The 18th Nobel Prize in Physiology or Medicine of the new century was awarded to the two pioneers of this insight, and the subsequent flow of mRNA vaccines, CAR-T, and gene editing has expanded upon this foundation.

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