Four Fables about Tumor Immunotherapy

Tumor immunotherapy is a new hot spot in the field of cancer. Its success marks that the human anti-cancer struggle has entered the third stage. The guidelines and evaluation criteria have all changed.

I have designed four fables to help everyone understand what is new about this new therapy, what is good about what, and what is wrong with the Chinese way of coping.

Fable 1

Once upon a time, there was an ancient country on the earth with a large population, poor resources and weak national strength. It was often harassed by its neighbors.

The old king decided that it was necessary to unite as one and enrich the country and strengthen the army so that all the people could live a good life and the country could not be invaded by other races. So he raised taxes greatly and set aside a large sum of money to form a huge army, ready to annihilate the invading enemy at any time.

He also took out a sum of money to form a flexible and efficient police force, which is responsible for monitoring dissidents at home and preventing people from embezzling state property.

This strict policy of the old king had a very good effect at first. Although the common people could not make money, every family lived and worked in peace and contentment, and their life was relatively stable. This peaceful life lasted for a long time. Everyone gradually relaxed their vigilance and various new thoughts kept popping up.

As a result, a lively and ambitious young man appeared in the country. He was unwilling to lead a miserable life like everyone else. He decided to take risks to sell drugs. He soon made a fortune and led an enviable rich life. His success attracted a large number of imitators, and some officials were dragged into the water by him. The situation gradually lost control.

The old king was old and helpless in the face of the ferocious drug lords. He could only use the army to surround the drug lords’ lair. However, the wannabe under the drug lords had already received information and fled to other places to continue drug trafficking.

Seeing that the drug trade is becoming more and more rampant, the neighboring countries cannot sit still. They jointly elected a military strongman and led a multinational force into this ancient country in an attempt to seize this drug kingpin and exterminate this evil force.

However, the drug kingpin is very cunning and usually dresses up like an ordinary person. It is difficult to find his hiding place. However, the military strongman did not care about this. He adopted a strategy of killing 1,000 people by mistake rather than letting one go. He arrested and shot all the rich people in the country. Naturally, the drug criminals were doomed to death.

But the result is that the country’s economic development level has plummeted. The people are not living well and the people are complaining, but the drug problem has not really been solved, because the drug lords have trained many of their people to become their successors, and various imitators have taken advantage of the situation to take advantage of the situation. Drug trafficking has not stopped, but has intensified.

Medical Interpretation of Story One

If we compare a cancer patient to a country and cancer cells to drug traffickers, the above fable is a microcosm of the history of cancer treatment.

Cancer has a long history. Our ancestors tried many ways to deal with cancer, but all failed. The reason is that cancer cells are changed from healthy cells of the human body itself. The difference between the two is very small. It is difficult to find a weapon that only kills cancer cells but is harmless to healthy cells.

A doctor named W.H.Woglom once lamented this in 1945:

It is difficult for those who have not received biochemical or medical training to understand why cancer is so difficult to conquer. It is like finding a solvent that dissolves only the left ear without damaging the right one.

Since no such solvent can be found, the tumor can only be identified by naked eyes, so the only way to treat early cancer is for doctors to perform surgery to remove cancer tissue based on experience.

However, this method can only be used for solid tumors that have not yet spread, and its application scope is limited. Moreover, it is difficult for doctors to ensure that they can be removed completely. Recurrence occurs from time to time. This is just like the old king in the fable, who only knows how to send troops to besiege the drug lords’ lair and treat the symptoms but not the root causes. The result is definitely not much better.

Where did the world’s first solvent that can distinguish the left ear and the right ear come from? The answer is chemical weapons!

Originally, in order to prevent the Axis countries from taking the lead in using chemical weapons, the U.S. Military set up a chemical weapons research department during World War II, focusing on nitrogen mustard gas. U.S. Military doctors reported:

Once the subjects were exposed to this mustard gas, the number of white blood cells would plummet after a few days.

Two Yale University scientists saw the report and thought, since mustard gas can destroy the reproductive ability of healthy white blood cells, will it also kill cancerous white blood cells?

The logic behind this conjecture is very simple:

Scientists at that time did not know the essential difference between cancer cells and healthy cells. The only difference that could be used was that cancer cells divided faster than normal cells.

White blood cells are a group of cells that divide very fast. They are first affected by mustard gas, which shows that mustard gas has the ability to interfere with cell reproduction.

So scientists tried to use nitrogen-containing mustard gas to deal with cancer patients and achieved certain curative effects. This is the origin of chemotherapy.

So, where did the inspiration for radiotherapy come from?

The answer is a nuclear explosion!

It turns out that after the U.S. Military dropped atomic bombs on Hiroshima and Nagasaki, medical staff studied the survivors and found that their bone marrow hematopoietic function was destroyed first. Radiotherapy was born in this way. The logic behind it is the same as chemotherapy. (Note: Radiotherapy was tried before World War II, but it was really used to treat cancer on a large scale after World War II.)

Chemotherapy and radiotherapy can be considered as the first stage of cancer treatment, The reason why the birth process of these two methods is so thrilling, The reason is that scientists did not know how cancer occurred at that time, and did not know that gene mutation played a role in the evolution of cancer cells in how, so they could only rely on the power of these two poisons. The logic behind this was-as long as they could kill 1,000 enemies, it doesn’t matter if they hurt 800 themselves.

The anti-cancer struggle at this stage is very much like the foreign military strongman in the fable. He has strong combat effectiveness, but he lacks experience in dealing with drug lords. He only knows how to act rashly. As a result, both sides are often hurt. Although drug lords are destroyed, the whole country is also dying, leaving no more than a few breaths.

It is worth mentioning that early cancer doctors knew the side effects of chemotherapy and radiotherapy were large, so they often did not have the heart to use them on patients and stopped taking them immediately when they saw the slightest curative effect. As a result, cancer cells often came back, leading to the failure of most treatments.

For example, the success rate of chemotherapy for acute lymphoblastic leukemia was only a poor 0.07% at first, which was almost a waste of money.

Later, an American scientist named Howard Skipper solved the problem. He proved that the mode of action of anti-cancer drugs follows [first-order kinetics], that is, drugs with the same concentration can only kill the same proportion of cancer cells, not the same number.

Therefore, he suggested that doctors should not stop taking drugs because they are afraid of side effects, but must insist on continuous use of large doses or even multiple drugs at the same time. The medical profession adopted his idea and raised the effective rate of chemotherapy for acute lymphoblastic leukemia to more than 70% at one stroke.

The reason why chemotherapy and radiotherapy are still widely used in many countries is closely related to this new idea.

The same idea can be applied to that fable. If a country is really ill, it must apply strong drugs with heavy hands. Perhaps there will be miracles. Turkey under Kemal Ataturk is a good example. If politicians are always looking forward, indecisive and persistent, the result will be even worse.

However, this method is, after all, too ruthless and has large side effects, and its curative effect on many kinds of cancers is limited. Doctors urgently need to find more specific anti-cancer drugs, which requires a fundamental understanding of the pathogenesis of cancer.

Fable 2

The military strongman’s [scorched earth policy] failed, and the International Anti-Drug Alliance elected a new leader.

The new leader is much more sedate than the previous one, He made a list based on past experience, listing the unique characteristics of drug traffickers one by one, such as likes tattoos, likes to drive luxury cars, wealth grows too fast, etc., and then arrested people according to this new standard. The effect was indeed good, and a large number of drug lords were accurately captured. The country’s drug trafficking network was severely hit.

However, no matter how large the net is, it is inevitable that there will be a fish that will slip through the net. These people will soon find out the arrest rules of the International Anti-Drug Alliance. They will no longer get tattoos or drive luxury cars, thus speeding up the speed and efficiency of money laundering. Indeed, they have escaped capture and grown up again.

Because they are foreign troops and are not familiar with the local national conditions, the anti-drug coalition forces not only respond slowly, but also meet with resistance from local residents, believing that these foreigners have violated their sovereignty and instead helping drug lords evade capture.

In this way, the new round of anti-drug trafficking campaign suffered another disastrous defeat.

Medical Interpretation of Story 2

The second stage of cancer treatment began in 1953, when the double helix structure of DNA was discovered, and the genetic secrets came to light. Scientists soon realized that the reason why normal cells become cancer cells was because the genes in the cells had changed.

In 1970, the first oncogene was discovered by scientists. As the name implies, once activated, this gene will make the division of normal cells out of control and become cancer cells.

In 1984, scientists discovered the first Tumor Suppressor Gene. This gene is opposite to the oncogene. Its normal function is to inhibit the growth of tumor cells, so once it is inhibited, cancer cells begin to grow wildly and cancer appears.

Since then, scientists have discovered nearly 500 different oncogenes and nearly 900 different tumor suppressor genes. It is known that the human genome contains about 21,000 genes, which means about 6% of human genes are related to cancer, which is a bit large.

The reason is that most cancer genes are originally [normal] genes. Their duty is to stimulate and regulate cell division and growth, which is one of the most important physiological functions of organisms. The so-called [vitality] is reflected here.

But cell division is also an energy-consuming process, If mistakes are made frequently, precious resources will be wasted, which is why organisms have evolved so many genes responsible for stimulating cell division and growth, while evolving more genes responsible for monitoring cell growth. The latter is even more important than the former in a sense.

Finding oncogenes and tumor suppressor genes is equivalent to finding the difference between cancer cells and healthy cells. In other words, scientists have finally found the difference between the left ear and the right ear, which can suit the remedy to the case and develop so-called anti-cancer targeted drugs that only target cancer cells without harming healthy cells.

Since FDA approved Herceptin (also known as trastuzumab) developed by Genentech in 1998, a large number of targeted drugs have entered the market, opening the prelude to the second phase of cancer treatment.

Among them, the more famous targeted drugs include Novartis’s Glivec (also known as Imatinib) and AstraZeneca’s Iressa (also known as Gefitinib) in addition to Herceptin. They are all star drugs in various fields. On the one hand, they have prolonged the lives of many patients with advanced cancer, and on the other hand, they have made a lot of money for their respective pharmaceutical companies.

The emergence of targeted drugs has changed the paradigm of cancer research. Previously, cancer classification was based on primary tissues or organs. This is also a familiar classification, such as lung cancer or breast cancer. However, new targeted drugs require doctors to classify cancers according to their genotypes. One drug is only responsible for killing cancer cells of a certain genotype.

For example, although Herceptin is nominally called a drug for treating breast cancer, it can only be used to treat HER-2 positive breast cancer patients. Doctors must first determine that the patient’s breast cancer is caused by overexpression of HER-2 gene, not other reasons, otherwise it is invalid.

As the saying goes, the advantage of targeted drugs lies in the specific action site, which only kills cancer cells. Doctors can give drugs in large doses without worrying too much about side effects. However, it is also because of the specific action site that the indication range of targeted drugs is often relatively narrow (don’t forget, there are 500 oncogenes alone).

Pharmaceutical factories have worked so hard to develop a targeted drug and spent a lot of money to apply for listing, but it can only be used for a few types of patients. Therefore, the prices of targeted drugs are mostly extremely expensive, bringing great pressure to medical insurance.

This is not the most important thing.

Due to the specificity of the target drug action site, cancer cells can avoid the attack of the target drug and continue to commit crimes as long as there is a slight variation in the target position.

In fact, this has been fully reflected clinically. At present, most cancer-targeted drugs on the market usually have a significant decrease in efficacy after a period of medication, because cancer cells have developed drug resistance to it.

Of course, in theory, patients can continue treatment with a new targeted drug, but this is tantamount to further increasing the economic burden of patients. Patients who are not financially well off often have to give up treatment.

Targeted drugs are just like the new leader in the fable. Although past experience can be used to find out the life rules of drug traffickers and then target the enemy, drug traffickers are not all fools and will also adapt to changes, thus escaping capture.

In this thrilling battle, one side is a well-equipped foreign army, and the other side is a native drug dealer. The former is not familiar with the local situation and its response speed is far behind that of the latter. If it cannot be killed with a single blow, it will definitely not be able to fight the local strongmen in the end and will not escape the fate of failure.

Fable 3

Seeing that foreign troops could not control drug traffickers, some people finally remembered that the country itself had police.

When the old king was young, he made great efforts to train a capable police force and kept the law and order well. Unfortunately, when the king was old and neglected management, drug traffickers finally took advantage of the loopholes.

However, these policemen are all native locals who are more familiar with the surrounding environment and have far more potential than foreign mercenaries. Therefore, the Anti-Drug Alliance pays for the police to be sent abroad in stages and batches to teach them how to use the most advanced weapons. After the training, they will be sent back to China to be the first in the anti-drug struggle.

However, the wishful thinking of the anti-drug alliance soon fell through. Although the fighting capacity of these policemen has improved, drug traffickers have bought them off with money.

Knowing this, the anti-drug alliance quickly changed its strategy and rewarded the police with more money than drug traffickers, but the effect was still not good.

It turns out that the most powerful trick of drug traffickers is not to buy off the police, but to buy off lawyers. The original duty of these lawyers was to prevent the police from abusing their power, but after receiving the money, they turned into military advisers of drug traffickers. They formulated a series of laws and regulations that favor drug traffickers and bound the hands and feet of the police.

As a result, the anti-drug alliance revised its strategy again, arrested a large number of corrupt lawyers and amended relevant laws, clearing the way for the anti-drug police. This finally saw the effect. A large number of drug traffickers were arrested, the drug trafficking network was completely destroyed, and the drug problem was finally solved.

Medical Interpretation of Story 3

Considering that the inherent drawbacks of targeted therapy are difficult to eradicate, some imaginative scientists have a brainwave. Why not use the human body’s own immune system to deal with cancer cells?

This idea is not new and has a history of more than 100 years. According to documentary records, as early as 1891, a New York doctor named William Coley tried to treat cancer with bacterial infection-he believed that bacterial infection could activate the patient’s immune system and attack cancer cells from the inside.

Later, some people made statistics and found that the curative effect of Corey’s therapy was almost the same as that of radiotherapy and chemotherapy. However, this method had many loopholes in theory and was too dangerous to operate. Therefore, it was quickly replaced by radiotherapy and chemotherapy and had not been used for a long time.

As the limitations of radiotherapy and chemotherapy gradually emerge, some people think of the immune system.

New research has found that, The human immune system is not only able to deal with foreign enemies such as germs and viruses, but also shoulders the mission of monitoring and cleaning up its mutant cells. In fact, healthy cells may be transformed into cancer cells in the human body every moment. Cleaning up these cancer cells is one of the daily tasks of the immune system, even more important than dealing with foreign enemies.

This is how a new round of cancer immunotherapy fever began. In 1984, American scientist Steve Rosenberg activated the immune system of patients with high doses of interleukin, and achieved success in some cancer patients.

At the same time, some people tried to activate the immune system with interferon, which also benefited a few cancer patients. These therapies are essentially replicas of Corey’s therapy, except that doctors no longer use germs, but use some known immune regulatory factors to activate the immune system, but the effect is not as good as hoped.

This is like the fable that the government pays the police, but drug dealers will do the same.

Scientists have come up with another trick, drawing out the patient’s blood, then separating the lymphocytes from the patient, culturing them separately, expanding them in large quantities in an in vitro environment, activating them by various means, and then transfusing them back into the patient’s body, hoping that they can become cancer cell killers, but unfortunately they still failed.

T cells are responsible for monitoring and removing cancer cells in the human body. T cells are a large category of immune cells with quite complex functions. Only T cells that can recognize cancer cell surface antigens can be used to deal with cancer.

Professor Jun Guo, Vice President of Peking University Cancer Hospital and Director of Renal Cancer and Melanoma Internal Medicine, explained:

This method belongs to non-specific immune activation, also known as [adoptive immunity]. There are all kinds of activated T cells. There are very few T cells that can really recognize tumor cells, and the specificity is too poor.

This method is equivalent to the fable of sending the police to foreign countries for training, but there are all kinds of police who participate in the training, and there are not many who are good at drug control. Therefore, this method is essentially equivalent to killing the left ear and the right ear together. The treatment concept has returned to the level of radiotherapy and chemotherapy, and the curative effect is naturally not much better.

More importantly, subsequent studies have found that the immune system can not only be activated but also suppressed. If the immune system is compared to a car, to make it run, it must not only step on the accelerator but also release the brake.

Many cancer cells escaped the encirclement and suppression of the immune system not because the immune system did not recognize the cancer cells, nor because the immune system was not activated, but because the cancer cells evolved a special method and secretly stepped on the brake!

The first important braking system was first discovered by French scientists in 1984. The main character of this system is a protein called CTLA-4, which is located on the surface of T cells and does not work at ordinary times. However, if it specifically binds to CD80 or CD86, it will start the braking function and prevent T cells from being activated.

The second important braking system was discovered by Japanese and Chinese scientists respectively. First, Professor Yusu Honjo of Kyoto University in Japan discovered another protein with braking on the surface of T cells in 1992. It was named PD-1. Later, Chinese-American scientist Professor Zhan Ping discovered the receptor protein paired with PD-1 in 1999 and named it PD-L1. This system is more powerful than the previous system. When PD-1 and PD-L1 specifically bind, T cells will start the suicide procedure and kill themselves before they go to the front line.

It must be explained here that this article involves many different proteins, and their names are difficult and unnecessary to translate, because all scientists and clinicians around the world have become accustomed to using their abbreviations to communicate, so the original meaning of these names is no longer important, let alone ordinary readers.

Organisms have evolved so many brake systems to prevent the immune system from losing control and blindly attacking itself. Some people have used gene knockout methods to breed mice without CTLA-4 protein, only to find that they all died of various autoimmune diseases before reaching adulthood.

These brake proteins are just like the lawyers in the fable. Without their supervision of police power, the life of ordinary people would have been even worse.

The discovery and application of brake protein must be thanks to one person, who is Professor James Allison, an American immunologist. When CTLA-4 protein was first discovered, everyone regarded it as one of many immunoregulatory molecules and did not attract enough attention.

Professor James Allison

Aresen is one of the few exceptions, He found that this molecule is different from other immunologically active molecules. When activated, it inhibited the activity of T cells. So he thought that the reason why the immune system turned a blind eye to the cancer cells appearing in the body and did not respond to how stimulation was probably that the cancer cells secretly stepped on the brake, preventing the immune cells that were originally responsible for monitoring cancer cells from being activated.

In 1996, Professor Aresen published a paper in the journal Science, which proved for the first time that antibodies against CTLA-4 can cure malignant tumors in experimental mice. He called this therapeutic idea Checkpoint Blockade.

To the effect that the immune system has to go through several checkpoints before launching a large-scale attack to prevent the wrong target. Cancer cells have stolen the system and kept the immune system unable to pass the checkpoint. All doctors have to do is remove (block) the checkpoint and release the vitality of the immune system.

The idea put forward by Professor Aresen is too advanced. It was not until 1999 that a small biotechnology company called Medarex bought all the CTLA-4 antibodies developed by Aresen and started human trials.

Pfizer, a pharmaceutical company, took a fancy to one of the monoclonal antibodies called Tremelimumab and bought its patent from Medarex. However, clinical trials found that the tumor volume became larger after the patient took the medicine. Pfizer scientists gave up the antibody in disappointment and did something else.

Almost at the same time, Bristol-Myers Squibb took a fancy to another CTLA-4 antibody called Ipilimumab and conducted clinical trials with Medarex scientists.

As Pfizer’s scientists have experienced, the clinical trial started with a rough start, with the patient’s tumor volume appearing to be larger than before. Just as Bristol-Myers Squibb was also planning to give up the drug, a patient took the doctor in charge of the clinical trial by the hand and said:

Don’t pay too much attention to the images on the X-ray film. What I want to tell you is that my body feels great.

This sentence made the doctor hesitate for a moment. He decided to wait, thinking that perhaps the curative effect of this medicine would take some time to show. The result really gave him a right guess. Two months later, the patient went to take a film again and found that the tumor volume was significantly reduced. The medicine worked!

Further research found that the reason for the increase in tumor volume at the initial stage of treatment was that a large number of activated anti-cancer T cells entered the tumor, so the increase in volume was a good thing, indicating that the patient’s immune system began to work.

Even better, The patient’s tumor continued to shrink after drug withdrawal, In the end, it almost completely disappeared. Now the patient is still alive and the tumor shows no signs of recurrence. You know, this patient is suffering from melanoma, and it is advanced. Normally, this kind of patient can only live for a few months at most. The 5-year survival rate of the existing treatment plan is only 10% ~ 15%. Generally, the patient with this disease is almost equal to the death penalty.

Professor Jun Guo, a recognized authority on melanoma in China, explained:

For cancer, we generally do not say cure, but say [partial remission] or [complete remission], which is equivalent to turning cancer into a chronic disease, and patients can live like normal people.

Melanoma is not very sensitive to chemotherapy, and the best chemotherapy drugs currently available have only a 7% effective rate, and cases of complete remission are extremely rare.

However, the new generation of immunotherapy drugs based on [checkpoint blocking] can already reduce the tumor volume of 70% ~ 80% of patients, partially relieve more than 40% of patients, and even achieve complete remission of about 10% of patients. This is a very remarkable achievement.

In 2009, Bristol-Myers Squibb spent 2.4 billion US dollars to buy Medarex, which is recognized by the industry as the most cost-effective deal in the pharmaceutical industry in recent years.

In 2011, FDA approved Ipilimumab to be listed in the United States as a drug for the treatment of advanced metastatic melanoma under the trademark Yervoy.

Bristol-Myers Squibb was initially priced at $120,000 a course (4 needles), which was definitely not cheap, but as the only effective drug for advanced melanoma, patients had to pay for it obediently. Although the total number of eligible patients was not large, Yervoy still made a lot of money for the company, with sales reaching $960 million in 2013 alone.

Science, published at the end of 2013, rated this kind of tumor immunotherapy drug based on [checkpoint blocking] as the first of the top ten scientific breakthroughs of the year, causing widespread concern.

Explaining the decision, the editor-in-chief of Science said that they generally did not award the award to a new drug that had just come on the market, but such drugs did not directly target tumors, but mobilized the human body’s own immune system to participate in attacks, which was a revolutionary breakthrough in therapeutic thinking and had great potential. This was the decision to break an example.

CTLA-4 is an early checkpoint in the immune response, If the gates were to be released at this stage, There will be a large number of T cells activated, Not all of them are associated with cancer, so the side effects can be large. It turns out that Yervoy has brought serious side effects to some patients, such as colitis and pituitary inflammation. However, since the medical profession is very knowledgeable about such inflammatory reactions and there are many drugs that can be used to relieve symptoms, the problem is not very big.

In contrast, PD-1 belongs to the late stage of immune response, and T cells specifically targeting tumors are often hit on the brakes. Therefore, at least in theory, monoclonal antibody drugs targeting PD-1/PD-L1 pathway have less side effects and should have greater advantages.

In fact, most pharmaceutical factories are currently focusing on the PD-1/PD-L1 pathway, and at least dozens of monoclonal antibodies against this pathway are under development.

In September 2014, FDA approved Pembrolizumab (trade name Keytruda), a PD-1 inhibitor produced by Merck Pharmaceutical Factory, for the treatment of advanced melanoma through fast channel.

In December of the same year, the same type of Nivolumab (trade name Opdivo) developed by Bristol-Myers Squibb was also approved for the treatment of advanced melanoma.

In 2015, former U.S. President Carter was diagnosed with melanoma, and the cancer cells had transferred to his brain, which was almost certainly hopeless in the past, but doctors prescribed Keytruda for Carter, and the tumor in Carter’s brain disappeared after a course of treatment.

This incident has made a live advertisement for this new therapy, which has once again aroused widespread enthusiasm among the public.

On March 4, 2015, FDA approved Opdivo for the treatment of metastatic squamous non-small cell lung cancer that still progresses after chemotherapy. Just six months later, FDA approved Opdivo for the treatment of metastatic non-squamous non-small cell lung cancer.

Keytruda was also approved for similar lung cancer in October of the same year. This is an important development in the field of cancer immunotherapy. Because the number of melanoma patients is too small, the number of Chinese patients is even smaller, but lung cancer is different. Especially in China, both the incidence rate and the death toll are at the top of the list. If Chinese patients can use the latest anti-cancer drugs, the number of people saved will be large.

Unfortunately, things are often not as good as everyone thinks, especially in China.

Fable 4

Seeing the success of the anti-drug campaign, other countries with similar problems followed suit, but the results were different due to different national conditions.

Some countries’ anti-drug bureaus only recognize money, but they continue to send police abroad even though others have proved that the training of police abroad is useless, because doing so can secretly make money. Politicians in some countries are cautious and worry that the power of the police is too strong to manage well. They have been afraid to give too much power to the anti-drug police, thus greatly reducing the anti-drug effect. Other countries only know mechanical imitation and do not know how to deal with it flexibly according to their own national conditions.

For example, the common people in this country generally advocate freedom and do not think that drug abuse is not good for what. They often help drug traffickers. At this time, if all the anti-drug tasks are handed over to the local police, the effect will naturally not be good.

Medical Interpretation of Story 4

So far, at least 6 kinds of tumor immunotherapy drugs based on checkpoint blocking have been listed in the United States, with a total accumulation of more than 50,000 cases, with a total effective rate of about 30%. Among them, 5% ~ 10% of the patients have maintained their curative effect for quite a long time, and many patients have survived for more than 10 years, indicating that T cells in their bodies have acquired some immune memory.

Just like vaccination, the curative effect can be maintained even after withdrawal. What is even more valuable is that the vast majority of the current cases are advanced patients with melanoma and lung cancer, both of which are notoriously refractory. In the past, almost all such patients were sentenced to death, but now they have new hopes.

Melanoma is a kind of cancer with strong immunogenicity, that is to say, the cancer cells carry a lot of tumor antigens on their surfaces and are easily recognized by the immune system. The same is true for lung cancer, especially lung cancer caused by smoking, which is also very immunogenicity, which is why the new generation of tumor immunotherapy drugs begin with these two kinds of cancers.

Professor Wang Jie, Director of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences, said:

However, this does not mean that immunotherapy drugs can only deal with these two cancers, because such drugs activate the patient’s own immune system and can theoretically be used to deal with all immunogenic cancers.

However, the history of new drugs is not long enough, and more cases need to be accumulated. I believe that with the accumulation of experience, this drug will be used to treat all cancers sooner or later, and the market potential is huge.

This is not Professor Wang’s idea alone, but the consensus of the entire medical profession. As a result, cancer immunotherapy has become the hottest research field in the medical profession, attracting a large amount of investment. There are a lot of new drugs waiting in line for clinical trials at home and abroad, which is really a grand occasion.

However, Professor Jun Guo believes that tumor immune drugs are not omnipotent, It is impossible to completely replace the existing targeted drugs. He believes that the existing tumor immune drugs usually take 4 months to take effect, which is simply too late for some emergency patients. At this time, targeted drugs specially aimed at tumor gene mutation should be used to control the disease condition first, and the use of immune drugs should be considered when the disease condition is stable.

Professor Wang Jie pointed out another shortcoming of immunotherapy:

At present, the curative effect of this new drug is still not ideal, only about 30%. The main reason is that the molecular markers for predicting the therapeutic effect and survival cannot be determined, so it cannot be regarded as personalized accurate treatment.

At present, another treatment method for lung cancer-targeted therapy has an effective rate of 70% ~ 80% for patients carrying corresponding target gene variations, and the probability of patients spending money in vain is greatly reduced.

In other words, the biggest advantage of tumor immunotherapy at this stage is that it has a wide range of adaptability and is good at fighting hard battles. It can also treat advanced cancers that cannot be treated by other drugs.

The disadvantage is that the curative effect of drugs needs to be improved, and patients may spend money for nothing, but once effective, the effect will often be especially good. Therefore, an urgent problem facing this field is how to find a special biomarker, which can help clinicians to accurately and quickly select the patients most suitable for immunotherapy.

However, the advantages and disadvantages of so many tumor immunotherapy discussed above are like flowers in the water in the well for Chinese patients, because so far no tumor immunotherapy drug has been approved by the China Food and Drug Administration to be listed on the mainland, and domestic patients can only go abroad or go to Hong Kong and other places to buy.

The problem is that such prescription drugs must be taken under the guidance of doctors, and doctors in regular hospitals dare not take them, so patients can only go to some private hospitals for treatment, which not only greatly reduces the level, but also is likely to encounter cheats.

According to the current situation, Bristol-Myers Squibb’s Nivolumab is most likely to become the first tumor immunotherapy drug approved for listing on the mainland. Professor Wang Jie has joined the clinical trial team of the drug and plans to start testing on lung cancer patients in China in early 2016.

However, such clinical trials are registered clinical trials, That is, it is specially carried out for the registration and listing in China. Foreign countries already have a lot of data for reference, so the innovation is not high from a scientific point of view. Even so, such registered clinical trials have to go through more than a year of examination and approval before they can be allowed to be carried out, plus various procedures before and after, Chinese patients are estimated to have to wait another 5 years.

Professor Guo Jun said:

At the beginning, Bristol-Myers Squibb once found me and invited me to join the global multi-center clinical trial in Nivolumab, but it took more than a year for China to approve the project alone.

However, neighboring countries including Japan and South Korea, as well as Taiwan Province of China, only need one month, so people can’t wait at all and can’t help it. I have to give up this precious opportunity.

Because the approval is too slow, China has missed countless such opportunities. As a result, the gap between China’s new drug research and the world’s advanced level is widening.

Chinese scientists can never stand on the international platform to report their research results to the world, and Chinese patients can never take the latest drugs in the first place.

According to Professor Guo, foreign countries have experienced five innovations in the treatment of melanoma. From targeted drugs to immunotherapy drugs to various combinations of combined drugs, each time is better than the other. At present, China has not even approved a targeted drug, which means that Chinese patients are not eligible to enjoy the results of the first innovation.

It is said that the slow approval speed of China’s Food and Drug Administration, In order for foreigners to test drugs first, To ensure the life safety of Chinese patients. This reason may be reasonable in other diseases, but it is totally unreasonable in the field of cancer, because most cancers are still incurable diseases, and many advanced patients are almost waiting to die. They are really willing to be [mice] of pharmaceutical companies, so there is still some hope.

According to Professor Wang Jie, most of the new tumor immunotherapy drugs approved by FDA in the United States are fast-track. As long as Phase I and II clinical trials show good safety and efficacy, sometimes they are approved to go on the market before even Phase III clinical studies have been carried out.

On the one hand, this is because the initial efficacy of the new drug is too good, The demand of patients is strong. On the other hand, it is because this drug was originally developed for advanced cancer patients who lack treatment methods. It can be approved for listing first, and then the curative effect of this drug can be further investigated in practice to collect adverse reaction data. This is the so-called concept of [Phase IV Clinical].

This practice has become quite common in the field of international cancer research, but the domestic regulatory authorities have not been able to conform to the international standards.

Another argument is that the reason why China’s Food and Drug Administration is strict is that Chinese pharmaceutical companies fake too much. However, Professor Jun Guo believes that this statement is also untenable.

There are fake cases in any country, and China may have more, but this should not be a reason to delay clinical trials.

Foreign countries generally adopt the method of low entry threshold in the early stage, but strict examination in the later stage, so-called lenient entry and strict exit. Moreover, once fraud is found, heavy penalties will be imposed, even causing you to go bankrupt.

This set of ideas has proved to be very effective, and China should learn from others. Fortunately, we have heard that China’s Food and Drug Administration is brewing a major reform recently to speed up the pace of clinical trial approval, and we are all eagerly looking forward to the early arrival of this day.

Professor Guo said so.

Interestingly, although China is cautious in the introduction and research and development of new drugs, it is extremely lax in the management of other drugs.

For example, the concept of tumor immunotherapy has been very popular recently, and many hospitals provide patients with what is said to be the most advanced immunotherapy in the world under the banner of immunotherapy.

But according to an insider who declined to be named, These hospitals actually use the above-mentioned method of in vitro culture of immune cells, Although this method cannot be said to be pseudoscience, This idea is still being studied internationally, but foreign countries have proved as early as more than 10 years ago that the effect of early immune cell therapy alone is not good, and the China Food and Drug Administration has not approved the clinical use of this method, but some domestic hospitals (especially military hospitals) openly provide this service to patients.

Of course, if it is a clinical trial study, it is not impossible, but then there is no charge. These hospitals not only openly use this unproven therapy on patients, but also charge high treatment fees, which is illegal in any country.

This is the current situation of Chinese medicine.


Cancer was once considered incurable, But since the discovery of oncogenes and tumor suppressor genes, The scientific community has begun to blindly optimistic that the secret of cancer has been cracked. Professor Douglas Hanahan and Professor Robert Weinberg, two top figures in the field of cancer, jointly published a final review article in the journal “Cells” (< >) in 2000, proposing the monoclonal theory of cancer.

According to this article, All malignancies begin with a [Renegade Cell], This cell has six characteristics due to gene mutation, namely, stimulating its unlimited growth, ignoring other bans, evading the cell suicide mechanism, evading the restriction of chromosome telomere length on the number of cell divisions, developing a blood supply system to maintain its growth, and having the ability to invade other tissues.

This monoclonal theory attempts to bring all cancers into the same simple and complete system, just as theoretical physics does.

However, shortly after the article was published, it was discovered that the cancer cells in the tumor did not all come from the same clone, but contained various kinds of cancer cells.

These cancer cells are not all caused by gene mutations, It also includes gene recombination, fragment deletion and DNA methylation. More interestingly, There are not only cancer cells but also a large number of healthy cells in the tumor. All these cells together form a complex microenvironment, and even microorganisms in the body will participate to jointly build a complex signal network suitable for the survival of the tumor.

On this basis, some people put forward a new cancer theory-evolution theory.

This faction believes that:

The occurrence and growth of tumors fully conform to Darwin’s theory of natural selection and are a process of continuous evolution.

Specifically, all cells in the human body are like individual lives, with various genetic variations occurring at any time. These variations endow these cells with different traits. These traits are selected in the body. The faster the division speed is, the better the cells are at evading immune supervision, the more chances they will have to survive and eventually become cancer cells.

This process keeps repeating, and cancer cells gradually acquire one unique trait after another. The number is increasing, and the tumor grows bigger and bigger, just like a species is selected by nature.

The only difference is that tumor cells are part of the organism. This selfish behavior of cancer cells eventually hurts the organism, and finally everyone can only end up together.

Anyone who has studied biology knows that Darwin’s theory of natural selection is the basis of all life processes. The reason why the earth has become so colorful as it is today is all because Darwin’s theory of evolution is at work. However, evolution also acts on the interior of multicellular life, and the emergence of tumors is the result of this theory’s prediction.

There is a famous saying in the movie Jurassic Park:

Life will always find its own way out.

Cancer cells are also life and will also find their own way out. This is not because cancer cells are very smart, but because the theory of survival of the fittest gives cancer cells tenacious vitality.

Therefore, the struggle between human beings and cancer will definitely continue. Scientists must be prepared to fight a protracted war, try new methods with an open mind, dare to try and make mistakes, and make progress in failure. Just like the three stages of tumor treatment mentioned in this article, each progress is the result of numerous failures.

This logic can also be used in that fable.

The spread of drugs will lead to the collapse of the society and the destruction of the country, but this is not the result that the drug dealer wants, because he will also die with him. However, every drug dealer will take chances and hope that he can make a lot of money and lead a rich life without affecting the country. This is due to human nature and is the case all over the world.

At this time, a strong government is needed to stop them and prevent them from succeeding. However, in the process of ruling, the government should also hold an open mind and never rest on its laurels. Instead, it should constantly correct its own mistakes, because the enemy the government has to face is the selfish nature of human beings, and this enemy is very strong.

This article is authorized by Sanlian Life Weekly to be published by Clove Garden.