The Power of Immunity and Cancer (Looking Back at the 2018 Nobel Prize in Physiology or Medicine)

Why do people get cancer even though they have an immune system that protects their bodies? The 2018 Nobel Prize in Physiology or Medicine was awarded to researchers who delved into this mystery and pioneered a new cancer treatment method that draws out the body's inner strength. The recipients were Professor Tasuku Honjo of Kyoto University and Professor James Allison of the University of Texas. The two discovered that molecules on the surface of immune cells act as a brake on the immune system. Cancer cells were using this brake to evade attack by immune cells. Furthermore, they opened the way to a new treatment method that can defeat cancer cells by blocking these molecules and restoring the immune system's attacking power.

The newly developed drugs are now widely recognized as the "fourth treatment" for cancer, playing a vital role in cancer treatment. How does the immune system work within our bodies? And how do cancer cells evade the immune system's attacks? Let's take a look at the immune system's "defense system" that protects our bodies every day.

Inside the body, cancer cellsExcluded

Cancer (malignant neoplasm) is the leading cause of death in Japan. The following three methods are known as the three main treatments for cancer: surgical removal of the tumor, radiation therapy to kill cancer cells by irradiating the tumor, and chemotherapy to kill cancer cells with drugs. What all of these treatments have in common is that they "directly target and attack cancer cells."

However, the "fourth treatment method" conceived by Nobel laureate Dr. Honjo and his colleagues is a different approach to treatment, one that "draws out the body's inherent immune power and allows the immune system to attack cancer."

Cancer is a disease in which the cells that make up our bodies, due to genetic abnormalities, lose their ability to cooperate with surrounding cells, divide and multiply uncontrollably, and destroy the body. Every day in our bodies, DNA is damaged by various causes such as carcinogens like tobacco, ultraviolet rays, radiation, viruses, and reactive oxygen species, or errors occur when DNA is replicated during cell division. As a result, cells can begin to divide uncontrollably.

In fact, cells that could become cancer cells are being produced inside the body, and these are being eliminated by various defense systems within the body. One of these defense systems that protects our bodies is the "immune system."

Immune cells constantly patrol the body, monitoring and eliminating foreign substances such as bacteria and viruses, as well as cancer cells. For example, dendritic cells, a type of immune cell, "eat" foreign substances such as pathogens and dying cells, playing a role in maintaining the body's normal state. These dendritic cells engulf and activate cancer cells, passing information about the cancer cells to T cells. The T cells then become activated and transform into "killer T cells," the attack force of immune cells, which recognize the cancer cells as foreign substances and attack them based on the information they have received. In this way, the mechanism by which T cells are activated is like stepping on the "accelerator" to increase the attacking power of the immune system.

The function of the immune systemThere are also "brakes" to keep things in check.

The immune system's role is to find and attack enemies, but if it becomes overly sensitive, it can also damage friendly cells. Therefore, the immune system has both an accelerator and a "brake."

For example, dendritic cells have a protein called "B7" on their surface, and depending on which protein on the surface of T cells it binds to, it determines whether it acts as an accelerator or a brake in the immune response. When it binds to a protein called "CD28" on T cells, it acts as an accelerator, activating the T cells. However, when it binds to another protein called "CTLA-4," it acts as a brake, suppressing the function of T cells. The number of CTLA-4 proteins increases as T cells become more activated, creating a mechanism that prevents T cells from overreacting. It was Dr. Allison and his research group who discovered this braking function of CTLA-4.

In addition to CTLA-4, T cells also have a brake called "PD-1" on their surface.

The brakes on the immune system「PD-1」

T cells are a type of lymphocyte within white blood cells, and their name comes from the fact that their role is determined by the "thymus" located above the heart.

In the thymus, T cells are "trained" to distinguish between their own cells (self) and foreign invaders (non-self). T cells that fail to mature properly die. Dr. Honjo and his colleagues were working on research to investigate this "apoptosis" of T cells.

"PD-1" was unexpectedly discovered during that research.

To unravel the mystery of PD-1, Dr. Honjo and his colleagues created "knockout mice" in which a specific gene was rendered inactive. They planned to observe mice with the PD-1 gene disrupted and investigate the effects. They found that around three to six months of age, the mice began to show symptoms such as dilated cardiomyopathy, a condition in which the heart muscle thins and widens, reducing its contractile force. This is known as an "autoimmune disease," in which the immune system mistakenly attacks the body's own tissues. The immune system's brakes were broken, causing the mice's immune system to run amok. This experiment revealed that PD-1 is an important gene that acts as a brake on the immune system, and their paper published in 1999 attracted considerable attention.

Cancer cells hit the brakes,Escape from the immune system

The doctor explained that cells that could develop into cancer are created every day, but are eliminated by the immune system. If that's the case, then why do so many people develop cancer?

In fact, cancer cells use various methods to evade the immune system. One of these methods is "misuse of the brakes." They hijack the braking function of the immune system and use it as they please.

Let's take a closer look at how PD-1, discovered by Dr. Honjo, acts as a brake on the immune system's attack on cancer. For PD-1 to function as a brake, a certain trigger is necessary. PD-1 has a pair of substances that act like a "key" and a "lock." When the key substance that fits into the keyhole of PD-1 binds to it, a brake signal is sent to killer T cells.

And surprisingly, cancer cells possess a key that allows them to bind to PD-1. Cancer cells expose a protein called "PD-L1," which pairs with PD-1, on their surface, effectively acting as a brake on the immune system and escaping attack.

Recent research has shown that PD-L1 can be released spontaneously by cancer cells or induced by substances released by killer T cells. When killer T cells recognize cancer cells, they release a substance called "IFN-γ." This substance was found to induce PD-L1 on the surface of cancer cells.

Release the brakes on the immune system,Exploring new avenues for cancer treatment

Dr. Honjo and his colleagues discovered PD-1, and in the United States, co-Nobel laureate Dr. Allison was investigating how CTLA-4, another brake on the surface of T cells, suppresses the immune system.

When knockout mice were created by disrupting the CTLA-4 gene, they developed symptoms of autoimmune disease and died about five weeks after birth. This confirmed that the gene functions as a brake on the immune system, similar to PD-1.

Like PD-1, CTLA-4 sends a brake signal to a cell when a key substance binds to it. Dr. Allison therefore devised a method to block the key from binding to the lock before it does, thus disabling the brake. He created a substance called an "anti-CTLA-4 antibody" that blocks the function of CTLA-4 and administered it to mice transplanted with cancer cells, such as colon cancer cells. He discovered that the cancer cells disappeared or shrank as a result.

Boost your immunityDeveloping cancer treatment drugs

Meanwhile, Dr. Honjo had also begun to consider whether creating an "anti-PD-1 antibody" that similarly blocks the function of PD-1 could be used to treat cancer. This would involve interfering with the binding of PD-1 and PD-L1, thereby preventing the attack of killer T cells from being inhibited. Drugs that block the immune system's inhibitory function and enhance immunity in this way are called "immune checkpoint inhibitors."

Dr. Honjo approached several pharmaceutical companies in Japan to seek collaboration in order to have this drug widely applied. However, most companies responded coldly. The reason was that various treatments marketed as immunotherapies, such as cytokine therapy and vaccine therapy, had not shown much effectiveness. Therefore, pharmaceutical companies were reluctant to cooperate. Amidst this, he finally managed to team up with Ono Pharmaceutical Co., Ltd., a pharmaceutical company in Osaka that had initially refused, and together they developed an anti-PD-1 antibody. Subsequently, with the cooperation of Bristol-Myers Squibb, a major American pharmaceutical company, the immune checkpoint inhibitor Opdivo®, which targets PD-1, was finally launched in 2014. Currently, anti-PD-1 antibodies and anti-PD-L1 antibodies are used in Japan, the United States, and Europe to treat about 10 types of cancer, including malignant melanoma (a type of skin cancer), lung cancer, and renal cell carcinoma. It is thought that the types of cancer for which these drugs can be used will increase in the future.

Prior to the launch of Opdivo in 2011, Yervoy®, an immune checkpoint inhibitor targeting CTLA-4, was launched. A paper published in 2013 by an American research group showed that combining the two drugs enhanced their effectiveness. Subsequently, a study comparing survival rates in patients with malignant melanoma, comparing those who received either drug alone versus those who received both, showed that the 3-year survival rate after disease onset was 37% for those receiving Yervoy® alone, 56% for those receiving Opdivo® alone, but rose to 68% when both were used. Currently, these drugs are actually used in combination for malignant melanoma and kidney cancer.

The drug's effects last a long time.The side effects are mild.

Immune checkpoint inhibitors targeting PD-1 have three advantages over other treatments. First, they can be effective even against advanced cancers that don't respond to chemotherapy. Second, their effects are long-lasting. According to clinical trial results published in 2012, of 31 patients whose cancer cell proliferation was suppressed after six months of treatment, 20 did not experience a recurrence for more than a year and a half after discontinuing treatment. Third, their side effects are milder compared to other treatments. It is believed that patients' quality of life (QOL) after treatment is higher than with treatments such as radiation therapy and chemotherapy that directly attack cancer cells. However, they are not without side effects. Because this treatment removes the brakes on the immune system, caution is needed regarding autoimmune disorders, such as when the immune system goes out of control and causes organ damage.

On the other hand, there are challenges as well as positive aspects. "In the future, we need to research why the drug doesn't work for some people," Dr. Honjo cited as a challenge at the press conference. There are individual differences in effectiveness. It takes several months for immune checkpoint inhibitors to start showing effects. During that time, it is frustrating that it is not possible to determine whether the drug is working or not. If it were possible to make a judgment before or immediately after administration, it would reduce the burden on patients. Recently, attempts have been made to enhance the effectiveness of immune checkpoint inhibitors in patients who do not respond well to them by combining them with other treatments.