It can be traced back to at least 300 years ago when people began to use the immune system to fight disease. According to records, in 1718, a British diplomat’s wife observed in Istanbul that “human smallpox vaccination” was very popular in the area. This refers to grinding the acne scars of the smallpox patients into powder, or directly taking the pus from the patient and letting them contact normal people. People at the time did not know the working mechanism of the immune system, but they knew that this would reduce the death rate of 30% of smallpox to 1%-2%.
Soon after, humans made a major breakthrough in the prevention of smallpox. In 1796, Edward Jenner, a member of the Royal Society, used experiments to prove that vaccinia can make humans immune to smallpox – 23 individuals who were vaccinated with vaccinia will not be infected even if they were exposed to more risky vaccinations. Jenner himself is hailed as the “Father of the vaccine”, and his discovery has inspired future generations to study the immunity. In 1882, Ilya Mechnikov presented the first complete theory of immunity based on observations on phagocytosis. Louis Pasteur developed the corresponding theory of bacterial pathogenesis and brought rabies vaccine and anthrax vaccine to humans.
These geniuses have gained a worldwide reputation for their immunological research. In contrast, William Coley's is less famed. But in the field of cancer treatment at the time, many people have heard of his radical therapy. After analyzing a large number of cancer cases, Dr. Collet found that infections associated with malignant tumors seem to bring about a relief of the disease. Among them, there is a very obvious correlation between the symptoms of erysipelas caused by streptococcus and the relief of soft tissue sarcoma. So he decided to inject cancer or bacterial products into cancer patients to ease their condition.
In 1891, Dr. Collet injected streptococcus in a cancer patient whose condition could not be controlled by surgery. As he imagined, the patient's tumor size became smaller. So in the next 40 years of his medical career, he treated nearly 1,000 cancer patients and claimed to have achieved excellent results in osteoma and soft tissue sarcomas.
But the voice of doubt has never stopped. On the one hand, some patients who have been injected with bacteria die from sepsis; on the other hand, many doctors do not believe that simple bacterial products can have any effect on cancer treatment. Although Dr. Collet was eventually hailed as the "Father of immunotherapy," at his time, his treatment was called "Kole toxin." With the development of radiotherapy and chemotherapy, Dr. Collet's therapy has gradually been forgotten. The first association between cancer and the immune system ended in vain.
PD-1- A Lucky Discovery
Strange enough, many important scientific breakthroughs often come from lucky discoveries. As far as vaccinia vaccine is concerned, we now know that the pathogen that has been reduced in activity is a good starting point for vaccine development. The pathogen used by Jenner in the past year has been naturally "deactivated" and is extremely lucky. In the 1990s, another accidental discovery brought far-reaching influence to future generations.
At that time, Japan was one of the most important research centers of immunology. Many Japanese scientists discovered new cytokines, identified their related receptors, and clarified their signaling pathways, which made important progress in immunology. Professor Tasuku Honjo, Kyoto University, the Nobel Prize winner in 2018, is one of many immunology experts. His team identified the cDNA sequences of IL-4 and IL-5 and found AID enzymes that play an important role in antibody formation. More than 20 years ago, his team focused on the programmed cell death of cells.
A then graduate student named Ishiday Kanai took over the project. They obtained two cell lines (LyD9, a hematopoietic progenitor; 2B4.11, a T cell hybridoma cell) that underwent programmed death under special conditions, and made reasonable assumptions: if a programmed death initiates in the cell, then the corresponding RNA and protein synthesis will also initiate. If you can find these RNAs or proteins, you may find genes that play a key role in them. Following this line of thinking, the researchers screened a series of cDNAs that might be involved in programmed cell death, the first of which was named PD-1 (programmed cell death protein 1).
The researchers then performed a series of analyses to confirm the expression pattern of the PD-1 gene. From these data, they pointed out in the paper that "the activation of PD-1 gene may be involved in the classical process of programmed cell death." Due to the importance of PD-1 in cancer immunotherapy, this paper has been cited more than 1600 times so far. But at that time, no one realized the huge clinical potential of this discovery.
PD-1, Immune System and Cancer
Humans have linked PD-1 to the immune system, a few years later. In 1999, Professor Tasuku Honjo's team decided to knock out the PD-1 gene in mice to see what it does. Interestingly, half of the mice lacking PD-1 developed lupus-like symptoms, a serious autoimmune disease. The researchers concluded that the immune system in these mice was abnormally activated. In other words, PD-1 acts as a suppressor of the immune system in mice.
In collaboration with Prof. Tasuku Honjo, Professor Arlene Sharpe and Professor Gordon Freeman subsequently found the two ligands PD-L1 and PD-L2 of PD-1 and elucidated the signaling pathways involved in PD-1. Studies have shown that PD-1 does inhibit the function of T cells, which confirms the hypothesis of Professor Tasuku Honjo's research group. More importantly, the researchers pointed out in a paper by Nature Immunology that "in many tumor cell lines, the mRNA levels of PD-L1 and PD-L2 are up-regulated," suggesting that this pathway is associated with cancer.
When it comes to the application of PD-1 in cancer treatment, it is necessary to mention the name of Professor Lieping Chen. In 1999, his team at the Mayo Clinic first discovered PD-L1 (then known as B7-H1). Subsequently, his team used irrefutable evidence to show that PD-L1 is critical for tumor survival. In a 2002 issue of Nature Medicine, they found that PD-L1 is expressed on tumor tissues such as melanoma and lung cancer, and it can promote the apoptosis of tumor-specific T cells, making them unable to attack cancer cells. In a key experiment, the researchers also showed in the culture dish that antibodies targeting PD-L1 can reverse this apoptosis of T cells! Professor Lieping Chen’s team wrote forward-lookingly in the abstract of the paper, “These findings may lead to T-cell-based cancer immunotherapy.”
In fact, this is not the first time that humans have thought of treating cancer through the immune system. As early as more than half a century ago, Dr. Frank Macfarlane Burnet, Nobel Prize winner in Physiology or Medicine, proposed the theory of cancer immune surveillance. It is estimated that there are at most 3,000 cancer cells in the human body every day, and it is our immune system that monitor and kill them and prevent them from forming tumors.
This theory sounds very appealing, but few people can confirm it. From the current point of view, this is not surprising. At the time, conventional immunotherapy focused on tumor-specific antigens. Some scientists believe that once the immune system is exposed to these antigens, it will be like a car to step on the gas, the engine runs at high speed, and the tumor is immune to killing. However, as many people have pointed out, tumor patients have long produced numerous tumor-specific antigens, but they should have stepped on the accelerator to the maximum immune system, but they have not achieved the desired effect. This is because people at the time did not realize that in order for the immune system to take effect, it is necessary to remove its "brakes".
In recent years, significant advancements have been made in the development of new immune checkpoint inhibitors. FDA has approved five different monoclonal antibodies targeting the PD-1/PD-L1 pathway, namely, atezolizumab (a PD-L1 inhibitor), nivolumab (a PD-1 inhibitor), durvalumab (a PD-L1 inhibitor), avelumab (PD-L1 inhibitor) and pembrolizumab (PD-1 inhibitor).