James P. Allison of the United States and Tasuku Honjo of Japan have been awarded the 2018 Nobel Prize in Physiology and Medicine for their outstanding contributions to cancer research. Through their independent research, these two scientists (specialized in cancer immunotherapy) have uncovered the path to cure cancer by utilizing the body’s own immune system.
|In 1996, James P. Ellison and his team proposed the idea of an anti-CTLA-4 molecule, which is a reverse-acting molecule to reduce the functional capacity of the protein molecule CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) located on the surface of T cells; this could later cure skin cancer [Ref. 1–2]. |
On the other hand, in 1992, Tasuku Honjo, a researcher at Kyoto University in Japan, came up with the idea of a PD-1 (programmed cell death-1) protein molecule that is located on the surface of a T cell, similar to CTLA-4 system [Ref. 3]. Anti-PD-1 and anti-PD-L1 molecules are currently being used to treat various types of cancer as cancer therapeutic agents, by reducing the effectiveness of PD-1 molecules. Anti-CTLA-4 and anti-PD-1 molecules are called checkpoint inhibitors [Ref. 4].
What is Cancer?
Most of the cells in the human body perform the functions of their daily life through a fairly respectable process. In the same way that cells multiply through controlled cell division, they usually try to reduce cell proliferation through the process of apoptosis. They are so healthy cellular citizens that through contact inhibition they can measure the number of increasing cells that subsequently destroy themselves to make room for new cells. When this orderly process breaks down, the cells show abnormal characteristics.
In an uncontrolled manner, old or damaged cells survive and new cells begin to form, which are needless in a healthy body. This uncontrolled cell division and its proliferation are commonly called cancer. This defective and abnormal cell growth affects the regular function of cells, changes their size and nature, and forms tumors (Figure 1). After initiating from one organ, these abnormal formations spread over the other parts of the body. Many cancers form solid tumors, where the cells come together to form a solid lump. Blood cancer, also known as leukemia, does not usually form a solid tumor, rather it spread over the body through the blood.
According to the World Health Organization (WHO), about 18 million people are affected by cancer (Global Cancer Observatory, 2018) [Ref. 5], and one person out of three in the world’s economically developed countries will be affected by cancer in the near future.
The Emergence of Cancer
Cancer is a genetic disease; changes in the genes that control the regular function of our cells disrupt the normal growth or division of cells and cause cancer to take shape. Cancer-causing genetic mutations can be inherited from our parents. Our lifestyle and environmental issues play a special role in the progression of cancer. At the same time, the radiation of ultraviolet rays from the sun affects our skin cells, while smoking damages our lungs or other cells. However, there is a unique combination of these genetic mutations. Even within the same tumor, different cells may have different genetic changes.
Types of Cancer
Changes in the size or nature of any cell in the body do not cause cancer. In hyperplasia, for example, cells usually divide rapidly and increase in number, but when viewed under a microscope, they appear to be normal cells. When cancer first starts in any part of the body, the overgrowth cells form after the formation of tumor. When the growing cells confine to a specific area, the condition is called a benign tumor. On the other hand, when cancer cells merge into the bloodstream or inside the lymph node, and spread to other cells in the body through the process of metastasis, it is called a malignant tumor (Figure 2) [Ref 6].
The term “cancer” affects almost every part of the body, including more than 100 diseases and all potentially fatal. Among these, carcinoma, sarcoma, melanoma, lymphoma, and leukemia mainly show their destructive forms in the human body. Carcinoma-derived from the skin, lungs, breasts, pancreas, other organs, and glands. Lymphoma is a cancer of the lymphocytes. Leukemia is a blood cancer. It does not usually form a solid tumor. Sarcoma occurs in bones, muscles, fat, blood vessels, or other soft and connective tissues of the body. They are relatively unusual. Melanoma is caused by pigment cells in the skin.
The Evolution of Cancer Immunotherapy
Different treatments are used to cure cancer, depending on the nature of cancer and the stage of growth. Of particular note are surgery, radiation therapy, chemotherapy, and hormone therapy, some of which have been awarded previous Nobel Prizes and played a significant role in human welfare. such as hormone therapy for prostatic cancer (Huggins 1966), chemotherapy (Elion and Hitchings 1988), bone marrow transplantation for leukemia (Bone marrow transplantation, Thomas 1990), etc. But the nature and types of cancer cells are so diverse that it is not possible to cure them in a specific medical treatment.
In the late nineteenth and early twentieth centuries, the idea of invading tumor cells arose through the activation of our body’s internal immune system. The immune system is made up of such cells or chemicals, which get activated by infecting the body with bacteria, viruses, or pathogens from outside the body. But the impact of this effort is very little. Currently, this technique is being used to treat bladder cancer with some modifications.
In the last few decades, cancer immunotherapy has gained major attention, especially for the treatment of some specific types of cancers. The key is to unravel the basic mechanisms that control immunity through basic research on how the immune system can detect cancer cells and destroy them by invading cancer cells. The basic feature of our immune system is to protect the body from invading bacteria, viruses, and other infections by maintaining its individuality and eliminating them through the internal defense mechanism.
T cells, a type of white blood cells that plays an important role in this defense system. T cell receptors are bound to the cells’ external biological molecules or substances and regulate the immune system through interactions. However, there are extra protein molecules that reside at the outer surface of these T cells that help to accelerate (i.e. Accelerator) this immune response, while some other proteins slow down this process (i.e. Brake) that interferes with the complete functioning of the T cells and inactivate its immune response. The right balance of accelerator and brake is essential for controlling disease management, which protects the body from external attacks, and restricts the destruction of healthy cells by preventing excessive activation of the immune system.
The protein molecule CTLA-4 (cytotoxic T lymphocyte Antigen-4) located on the surface of the T cell acts as a brake. In the 1990s, James P. Allison of the University of California, Berkeley, first proposed the idea that CTLA-4 acts as a negative regulator in the activation of T cells. Later he developed antibodies of CTLA-4 called the anti-CTLA-4 molecule that could bind to CTLA-4 and inhibit its function. This anti-CTLA-4 molecule effectively destroyed the negative control or inhibitory potential of CTLA-4, resulting in the generation of highly activated T cells for invading cancer cells. In late 1994, James P. Allison and his colleagues demonstrated by experiment that these antibodies could cure tumors transplanted into mice (Figure 3) [Ref 1]. These results explored a new concept in Immunotherapy.
Despite the limited interest of pharmaceutical companies in antibody therapy, Allison continued his efforts to develop this technique in the human body, and later developed an anti-CTLA-4 IgG1 monoclonal antibody named MDX-010 based on transgenic mice in collaboration with the biotechnology company, Medarex, in 1999. Medarex is now under the company of Bristol-Myers Squibb continued the clinical development of this monoclonal antibody, now called ipilimumab. A significant clinical study in 2010 found a major breakthrough of anti-CTLA-4 in the treatment of unresectable metastatic melanoma and subsequently received approval from the FDA (The Food and Drug Administration) and the EMA (The European Medicines Agency) in 2011.
The effect of anti-CTLA-4 treatment in tumor-bearing mice compared to controls. A few years before Allison’s CTLA-4 discovery, Tasuku Honjo from the Kyoto University in Japan came up with the idea of a PD-1 (programmed cell death-1) protein molecule located on the surface of T-cells in 1992. But at that time, Hanjo and his colleagues speculated that PD-1 involves in the pathway that regulates the process of apoptosis . The exact efficacy of PD-1 was elusive for many years. Subsequently, Hanjo and his colleagues concluded through relentless research that the PD-1 molecule like CTLA-4 negatively regulates the immune response (Figure 4) [Ref. 7].
However, the regulation mechanisms are different. Generally, PD-1 has two ligands: PD-L1 and PD-L2 that bind to PD-1. Cancer cells contain large amounts of PD-L1 which binds to PD-1 located in T cells in such a way that T cell signals are transmitted to the recipients (T cell receptor signaling); therefore, efficacy is lost, which helps to prevent cancer cells from having an immune attack. Anti-PD-1 or anti-PD-L1 monoclonal antibodies block PD-1/PD-L1 binding, thereby increasing the immune response against cancer cells. Significant effects of this anti-PD-1 have been observed in the treatment of renal cancer, lung cancer, and melanoma. Recently, through clinical research, two different types of PD-1 antibodies, pembrolizumab (Merck) and nivolumab (Bristol-Myers Squibb) have been approved by the FDA and the EMA.
Antibodies that have the same ability to respond to tumors are now called immune checkpoint inhibitors (Figure 5 and Figure 6) [Ref 8].
Preventing immune response by blocking the efficacy of CTLA-4 and PD-1 in early research marks the beginning of a landmark chapter in clinical research and medicine. It is now called “Immune checkpoint therapy”. This therapy, like other cancer therapies, has adverse side effects too, which can be serious and even life-threatening. In general, over-reactive immune responses also accelerate various auto-immune reactions but these processes can be managed or controlled. Continuous research aims to improve therapy and reduce side effects. Of the two treatment strategies for treating a variety of cancers, including lung cancer, renal cancer, lymphoma, and melanoma, checkpoint therapy against PD-1 has shown more effective and positive results. Recent clinical studies have shown that the combination therapy is more effective by blocking both CTLA-4 and PD-1, as demonstrated in melanoma patients (Figure 7) [Ref. 9].
Cancer Immunotherapy: The Present Scenario
Allison and Honjo are presently working on combining different strategies to destroy tumor cells more effectively, by destroying the ability of different immune defense mechanisms. Checkpoint therapy or cancer immunotherapy is currently being applied against a variety of cancers and new checkpoint proteins are being tested. For more than 100 years, scientists have been trying to use the body’s own immune system to fight against cancer. Progress in clinical research was very modest until the basic discoveries of these two Nobel Laureates were made. Checkpoint therapy or cancer immunotherapy has now revolutionized the treatment of cancer for the benefit of mankind and added a new pillar to the existing cancer treatment (Figure 8) [Ref 8].
References (Cancer immunotherapy & related)
 Science. 1996, 271(5256):1734-6;  J Exp Med. 1999, 190(3):355-66;  EMBO J. 1992, 11(11):3887-95;  Front Oncol. 2018, 8: 86-99;  GLOBOCAN 2018 database, accessible at http://gco.iarc.fr/, IARC’s Global Cancer Observatory;  Diagnosis and Therapy. 2007, 19 (10): Clin. Oncol. 748-756;  Int Immunol. 2005, 17(2):133-44;  Press release: The Nobel Prize in Physiology or Medicine 2018;  N Engl J Med. 2017, 377(14):1345-56.