“Crazy” anti-cancer history: Experimenting with prisoners

“Crazy” anti-cancer history: Experimenting with prisoners. “Crazy” anti-cancer history: from using live bacteria to fight toxins and experimenting with prisoners, and finally achieving a Nobel Prize.

If the “crazy” doctors used bacteria to fight cancer and viruses to “eat” tumor cells for 100 years, we might not be able to understand the subtle relationship between tumors and the immune system well today. Then, the 2018 Nobel Prize in Physiology or Medicine will naturally not be awarded to the field of tumor immunotherapy.

introduction

On January 2nd, 2021, British doctor David Tucker reported a blockbuster “anecdote”: After a patient with malignant lymphoma was infected with the new coronavirus, the tumor was so scared that he was consciously “isolated” [1] . This 61-year-old man has been very depressed in recent years. He first suffered from severe kidney disease and finally failed a kidney transplant.

Left: before the COVID-19 infection; right: four months after the COVID-19 infection, picture source: Br J Haematol. 2021

In 2020, he was admitted to the hospital again because of lymphadenopathy, but he was diagnosed with lymphoma again, which was still at an advanced stage. It was a leak in the night, and not long after the diagnosis of lymphoma, the hateful COVID-19 fell to the ground again and extended its magic claws to this man.

The so-called misfortune and blessing depend on. Four months later, the man went back to the hospital for a review, and miraculously found that the tumor cells were like “lightly I am gone, just as I came gently”, most of them disappeared.

After various brainstorms, we have a bold conjecture in our minds. Could it be that the COVID-19 virus killed the tumor? This has to be reminiscent of the “father of tumor immunotherapy” William Coley and his crazy past.

From “the side door to the left” to a cross-age move

William Colley was a surgeon in New York at the end of the 19th century. When his career just started, Corley had a patient named Dahir amputation (Note: As for who Dahir is, I don’t need to introduce too much here, I just want to say that she was related to the famous Rockefeller), But within a year, Dashir still failed to resist the invasion of sarcoma, and unfortunately passed away.

After Dashir’s death, Corley was angry at his incompetence and turned his anger into strength, and went through the literature to find new ways to fight cancer. The effort paid off, and Corley finally found a glimmer of light: a sarcoma patient named Fred Stein was infected with erysipelas during the operation. Erysipelas is an infection caused by streptococcus. Antibiotics were not yet available at the time, and Stan could only handle it. Just as Stan was fighting the virus tenaciously, the sarcoma on his neck shrank.

Corley was very excited and looked up the literature more actively. Coincidentally, Corley found another 47 similar cases, so this is not a coincidence! As a result, William’s brain was wide open, and he boldly guessed that the bacteria might secrete a toxin that could kill cancer cells “with poison”.

In the beginning, Coli refined the streptococcal liquid, which is the most primitive “Coli’s toxin”. What needs to be added here is that there was no concept of clinical supervision more than 100 years ago. As long as patients are willing to be “white mice”, doctors can experiment freely.

In 1891, Colley ushered in the first “guinea mouse”: a 35-year-old Italian addict Zola had a large tumor on his neck (above), unable to eat, and unable to operate. Basically equal to the sentence of death. As a result, Coli’s dead horse was used as a living horse doctor, and Zola was injected with dozens of erysipelas before and after. Zola’s fever reached 41 degrees, but the good news is that his tumor has also begun to decrease, and only two weeks later, only left. There was a scar [2].

Coley took advantage of the victory, and successively treated ten patients with the same method, but some did not have a fever at all, some had a fever but the tumor did not change, and some were directly infected and died. But how could this setback stop Coley’s pace, he began to study a new formula, which is an upgraded version of “Coley toxin”, using two kinds of inactivated bacteria (Streptococcus pyogenes and Serratia marcescens) Replace the original live bacteria.

The “Coli Toxin” has treated nearly 1,000 people before and after, and the efficacy is unstable. In addition to the inability to explain why the toxin is effective for cancer, “Coli Toxin” has not been recognized by the academic circle, and even considered a side effect. Because the concept was too advanced, Colley could not be recognized by the medical community until his death in 1936, and then coincided with the rise of radiotherapy and chemotherapy, “Coli’s toxin” was naturally forgotten in a corner of history.

Fortunately, there is still one person in the world who has not given up.

After Coley’s death, his daughter Helen Coley Nauts (Helen Coley Nauts) spent her life systematically tracking the reports of her father and patients. In her 18 monographs, she identified more than 500 who were cured by her father. The case was successfully rehabilitated for her father, and the Cancer Institute was established in 1953 to commemorate her father and promote the development of tumor immunotherapy [3].

With the discovery of CTLA-4 in the 1980s, the relationship between “Coli’s toxin” and cancer began to slowly surface. Scientists have discovered that when immune cells want to attack cancer cells, CTLA-4 will jump out to stop them, but when the human body is infected, CTLA-4 obediently allows the immune cells to attack the virus and cancer cells. This explains “Coli Toxins may use the immune system to fight cancer.

The theoretical basis that Coley searched up and down finally got preliminary confirmation.

In 2010, the U.S. Food and Drug Administration approved Provenge, the first vaccine that uses the immune system to attack prostate cancer. In 2011, it approved the cancer immunotherapy drug CTLA-4 inhibitor Yervoy. So far, cancer immunotherapy has become a star. The highest honor award was also named the “William Coley Award” to commemorate the “father of cancer immunotherapy.” In 2018, two scholars in the field of tumor immunity won the Nobel Prize in Physiology or Medicine.

Centennial exploration of oncolytic virus

While Coley was working tirelessly with his “Coley toxin”, in 1904, Georgy Dock of the University of Michigan also published an interesting report: A 42-year-old woman with leukemia was infected with influenza virus, and her leukemia symptoms improved significantly [ 4].

It seems that cancer is really the target of public criticism. Bacteria is not pleasing to the eye, and viruses are not to be seen.

Immediately after 1912, Italian doctors on the other side of the Atlantic discovered that injection of rabies vaccine could cause cervical cancer to subside. These endless cases inspired doctors to explore the possibility of viral treatment of cancer and also gave birth to the concept of oncolytic virus. Literally speaking, an oncolytic virus is a virus that can “dissolve” tumors [5].

The first wave of oncolytic viruses was from 1950 to 1970. At that time, the clinical trial specifications were slowly established, and they were in the stage of crossing the river by feeling the stones. Coupled with the anxiety of rushing to the hospital, doctors would be simply and rudely affected by the virus. The serum of the infected patient is directly injected into the cancer patient’s body. As a result, it is conceivable that there is no way to control the virus. Some patients die directly because of the infection.

At the same time, Alice Moore of the Sloan Kettering Memorial Center became the first scientist to apply the concept of oncolytic virus to animal models. He also obtained more efficient virus strains through continuous virus passaging experiments, which The advancement of oncovirus research to a more scientific and safe direction has also paved the way for genetically modified oncolytic viruses.

Moore has tried different types of viruses, such as influenza virus, vaccinia virus, and herpes virus (the main “culprit” in mouth bubbles after eating hot pot), etc., and has also published numerous research papers, and waved the flag to drive a group of people to participate. Research on oncolytic virus. Unfortunately, there is a huge technological gap between ideal and reality, and the clinical results are still not ideal.

EGYPT 101 virus treats cancer patients, picture source: C. M. Southam, A. E. Moore, Cancer, September 1952

Moore’s colleague Chester Southam is also one of the pioneers of oncolytic viruses. Because I was so obsessed with the relationship between the immune system and cancer, I madly injected Hela cancer cells into 65 healthy prisoners, trying to observe whether the prisoners can rely on their own immunity to defeat the cancer cells, and then secretly developed more Large-scale “clinical trials”. After the incident was exposed, it caused an uproar and became a must-learn negative teaching material for scientific ethics [6].

After the early rational and irrational exploration, oncolytic viruses finally hoped for a new dawn in the 1980s: the advent of genetically modified technology. In other words, you no longer have to look for a needle in a haystack to find a better oncolytic virus, you can directly transform the existing virus.

Compared with wild viruses, genetically modified viruses can artificially remove toxic genes to make it safer, or they can add special proteins on the surface of the virus to identify cancer cells or stimulate immune responses.

Since the first transgenic oncolytic virus was reported in 1991 [7], scientists from all walks of life all over the world have shown their magical powers.

What is surprising is that the United States, known as the “big science brother”, was on the oncolytic virus track by Latvia, which had to be seen with a magnifying glass on the map, took the lead.

As early as 2004, the Latvian government approved the world’s first oncolytic virus drug RIGVIR for the treatment of melanoma. In the second year, the improved adenovirus H101 was also approved in China. Although it was basically ineffective in clinical practice and was rejected by the US and European drug administrations many times, it still made a lot of money in China. After all, the safety is not bad. When buying a psychological comfort [5].

It was not until October 2015 that the prudent US Food and Drug Administration approved the first oncolytic virus drug T-VEC. Now that it has been officially recognized by Big Brother, it also marks that the oncolytic virus has entered a mature stage of arrogance.

Upgraded Armed Forces to “Fight with Drugs”

In fact, whether it is bacteria or viruses, it is not because they are friends of mankind. The reason why it can be used by our generation is entirely due to the greedy nature of cancer cells.

Where does this start?

When a virus etc. invaded the human body, at first it was a mad beating, grabbing the cells, and letting him get in there quickly. But normal cells are more alert. After the virus sneaks in, they feel uncomfortable. They start the “virus search” game. After finding them, they can open up the two channels of Ren and Du such as interferon to prevent the virus from causing trouble. If you encounter a stubborn molecule, even at the expense of yourself (cell apoptosis), you must not let the virus reproduce wildly. After self-sacrifice, normal cells still don’t forget to produce cytokines to remind the surrounding immune cells, and quickly come over and roll up their sleeves to work overtime.

But cancer cells are different, because one mind is busy eating, reproducing, and reproducing, and others can save money. Therefore, the most powerful anti-virus software such as interferon is not installed, which gives the virus the opportunity to take advantage of it. : There is such a peaceful place, don’t come here quickly. Therefore, compared with the difficult normal cells, the virus regards cancer cells as fertile soil.

After the virus enters the cancer cells, it begins to replicate and multiply in large numbers. After a while, it will literally “squeeze” the cancer cells like a balloon (cell lysis), and their children and grandchildren will further infect the surrounding cancer cells. In addition, the dying tumor cells will release some substances, such as tumor antigens, etc., which can allow the immune system to discover deeply hidden cancer cells and initiate anti-tumor immune actions.

The mirror of history has already told us that “fighting poison with poison” is a good idea. From a scientific point of view, how can we make the “fighting with poison” proficient?

First of all, the first point is naturally to send the virus fighters to the battlefield safely, during which there are real obstacles:

When the oncolytic virus enters the human body, most of it is collected by the liver within a few minutes, and only after successfully escaping can it enter the moat of the circulatory system.

Immune cells are planted in the moat to patrol all year round. Everyone knows about the immune cells and accepts death. Whether you are a “virus fighter” or a “virus killer”, as long as it is a virus, you will unselfishly direct the “neutralizing antibody” to catch the virus. After this tossing, the virus had to cross the mountains and ridges to cross the barriers around the tumor, squeeze in through the stitches, and finally reach the inside of the enemy.

Obstacles to oncolytic viruses, image source: Nature Reviews Cancer, volume 5, pages965–976 (2005)

Really don’t want to see the oncolytic virus so tired and turnover, the scientists decided to inject the virus directly into the tumor, such as the approved drug T-VEC mentioned above. Although this can escort the virus to the tumor to the greatest extent, if the tumor is hidden deeply, methods such as interventional imaging or surgical exposure are needed to locate, which adds additional pain to the already weakened patient.

So going around and around, the virus has to rely on itself for ninety-nine and eighty-one. All humans can do is design some high-end armors for it. For example, Oncorus, a biotechnology company based in Massachusetts, USA, wraps the oncolytic virus in lipid nanoparticles to escort the virus to escape the immune system.

Lipid nano-oncolytic virus, image source: Oncorus official website

In addition, the virus is a double-edged sword, which can be life-threatening if it is not used well. Fortunately, scientists will not repeat the same mistakes and directly inject wild viruses into patients, and they will also find ways to give the virus a double insurance. The most common is to unload genetic weapons that are toxic to normal tissues. For example, T-VEC is to knock out the γ34.5 gene of HSV-1. The γ34.5 gene is a secret weapon for viruses to escape from normal cells. After being knocked out, it is difficult to replicate in normal cells, thus ensuring safety [8].

The second strategy is to install a safety valve. For example, add an E2F-1 promoter to E1A, which is responsible for adenovirus replication. The E1A supervisor will only start work after receiving the E2F-1 approval. Cancer cells, including bladder cancer, just have the authority to approve documents, but normal cells do not, so the virus is controlled to replicate in the cancer cells.

Conclusion

There were records of vaccination as early as the Ming and Longqing period of the 16th century. Until the end of the 18th century, British doctor Edward Jenner accidentally discovered that milkers could barely get smallpox. The inspiration for vaccinia vaccination was born, and then the smallpox vaccine was officially promoted. .

Oncolytic viruses and other concepts of “attack poison with poison” are also practice first, and then the scientific theory is explored, and finally the unity of knowledge and action is achieved. This is closely related to the limitations of the technology at that time.

As for whether the COVID-19 virus can also become one of the candidates for oncolytic virus, it is better to enjoy modern technology.

Reference:

1.Challenor, S. and D. Tucker, SARS-CoV-2-induced remission of Hodgkin lymphoma. Br J Haematol, 2021.
2.Hoption Cann, S.A., J.P. van Netten, and C. van Netten, Dr William Coley and tumour regression: a place in history or in the future. Postgrad Med J, 2003. 79(938): p. 672-80.
3.Engelking, C., Germ of an Idea: William Coley’s Cancer-Killing Toxins. 2016.
4.Dock, G., THE INFLUENCE OF COMPLICATING DISEASES UPON LEUKAEMIA. The American Journal of the Medical Sciences 1904. 127(4).
5.Cao, G.D., et al., The Oncolytic Virus in Cancer Diagnosis and Treatment. Front Oncol, 2020. 10: p. 1786.
6.Hoyt-Disick, G.T.I.L.o.H.L.C.I., Immoral, and Deplorable.” LitCharts. LitCharts LLC, 29 Jun 2016. Web. 17 Jan 2021.
7.Martuza, R.L., et al., Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science, 1991. 252(5007): p. 854-6.
8.Zhang, B. and P. Cheng, Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol Cancer, 2020. 19(1): p. 158.

(source:internet, reference only)

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