Scientists have followed suit to open a new page in immunotherapy
In 1970, a 19-year-old Soldier in the People's Liberation Army contracted lymphoma, and there was no cure for it, and the receiving doctor had to try to treat it with hormones and nitrogen mustard.
Unexpectedly, after only three days of medication, the patient's lymph nodes disappeared and the fever receded.
Surprises are fleeting. A week later, the young man developed a high fever again and died 14 days later.
51 years later, in the early winter of 2021, the doctor who treated the warrior recalled this past at the first China Lymphoma Friends Conference: "At that time, I just started working, only hormones and nitrogen mustard were available in my hands, and it was difficult for patients to cure. ”
Professor Ma Jun, director of the Harbin Institute of Hematology and Oncology, has received countless patients in his life as a doctor, and his reputation in the blood and tumor community is gradually rising, and he has the reputation of "Golden Saint Fighter". Along the way, Ma Jun has witnessed lymphoma gradually become one of the tumors with the highest cure rate from an "incurable disease".
This experience also shows that the complete fight against a cancer is the result of the joint efforts of the whole world.
The battle of cancer unleashed by poison gas bombs
More than 100 years ago, the world was very unstable. During World War I, "mustard gas" was invented, and poison gas warfare spread to the battlefield.
Mustard gas can inhibit the body's hematopoietic function and cause death. At first, both sides of the war secretly dropped mustard gas bombs, and it was not until 1943, when the Germans bombed Bari, Italy, hitting an American ship carrying 2,000 poisonous mustard gas bombs, causing a large number of medical personnel and civilian injuries, and the U.S. military began to conduct in-depth research on mustard gas.
U.S. Marine Corps chemical warfare drug consultants have found that mustard gas destroys most of the body's white blood cells, can it be used to treat blood diseases?
The U.S. Office of Scientific Research and Development funded scientists to conduct related research. Pharmacologists Goodman and Gilman gave mice with lymphoma with mechlorethamine, and the mouse lymphocytes were killed and the lump shrank dramatically.
Subsequently, doctors began to use nitrogen thaliana to treat Hodgkin lymphoma and other lymphomas and leukemia, with great success.
Pictured: Goodman and Gilman
Nitrogen mustard became the world's first cancer chemotherapy drug, and a whole new world was opened.
The lymphoma treatment plan that Ma Jun chose at that time was nitrogen mustard, and the treatment of the Chinese medical community in this field was very early in line with international standards. But in practice, like doctors around the world, Ma Jun encountered a problem: nitrogen thaliazine is difficult to treat patients with recurrence, and the survival rate of patients cannot be improved.
Professor Ma Jun, Director of Harbin Institute of Hematology and Oncology
After experiencing that period of helplessness, Ma Jun recalled: "Until now, I did not dare to touch the nitrogen mustard again. ”
The first anti-cancer monoclonal antibody icebreaker
After the 1970s, scientists' understanding of the human immune system gradually matured, and how to use immune weapons to treat cancer became an important issue.
In 1975, Argentine scientist Milstein and German scientist Köhler fused normal B cells with myeloma cells to obtain hybrid cells that continuously produced specific antibodies, giving birth to hybridoma technology.
This became the starting point for humans to utilize the immune system. In 1984, the two were jointly awarded the Nobel Prize in Physiology or Medicine.
Pictured: Milstein and Köhler
With monoclonal antibody technology, the ideal target for the initial treatment of lymphoma is also targeted at the CD20 target.
CD20 targets can be found on the surface of many kinds of lymphoma cells, and countless scientists have begun to launch tentative attacks on lymphomas with anti-CD20 monoclonal antibodies, but almost all of them have fallen into the shadow of failure.
For more than a decade, scientists have gradually approached success through technologies such as genetic recombination. In 1997, rituximab, which targeted CD20 and treated lymphoma, was marketed, becoming the first approved anti-cancer monoclonal antibody.
This monoclonal antibody is "Merova". Few people know that the "Meiluohua" that later became famous for fighting cancer was born after several twists and turns, and was almost stillborn.
At that time, Professor Levy and colleagues at Stanford University founded a biotechnology company called IDEC to advance the study of CD20 monoclonal antibodies. Although the research has progressed quite smoothly, in the environment of the 80s, the more popular direction than lymphoma is lung cancer, and other anti-cancer monoclonal antibodies have also failed, and capital does not favor him at all, and it seems that he will not be able to go on because of lack of money.
In a pinch, a company that later became famous but was still unknown at the time came together with Levy, and this was Genentech.
Genentech was founded in 1976 by Nobel laureate and biochemist Herbert Boyer, the era when the biotechnology industry would be born. In a short period of time, Genentech has successfully developed recombinant insulin, somatostatin, growth hormone and other products. With the launch of the first monoclonal antibody, Genentech seems inevitable.
But, like many biotech companies, Genentech in the '80s was desperately short of money. In 1989, Genentech was in a "penniless" situation. Just then, a pharmaceutical giant threw out an olive branch: In 1990, Roche spent more than $2 billion to buy a 60% stake in Genentech, allowing Levy's research to continue.
Finally, in 1997, "Mei Luohua" turned out to be a success.
As the world's first listed monoclonal antibody for the treatment of cancer, the birth of "Meiluohua" has opened up a new cancer treatment method, changed the pattern of lymphoma treatment, and made the cure of lymphoma possible. In 2000, rituximab "Merova" entered China, only 3 years after it was listed in the United States. Ma Jun, who has witnessed the evolution of blood tumor treatment with his life, sighed:
"This is the first and most remarkable monoclonal antibody, it is so beautifully structured, ushering in a new era of immune-targeted therapy."
The fight against cancer is nirvana in defeat
More than 20 years later, when doctors meet, they still remember the surprise of their first encounter with "Mei Luohua". This epoch-making new drug has given more and more lymphoma patients the opportunity to live.
Eventually, "Merova" combined chemotherapy became the standard treatment for non-Hodgkin lymphoma, which was R-CHOP. The data show that if patients can achieve event-free survival at 24 months of treatment, the overall survival is close to that of healthy people.
Scientists and clinicians are pleased that about 70% of such patients are available.
As one of roche's three most successful monoclonal antibodies, "Meiluohua" has been one of the most successful drugs in the history of global pharmaceuticals since its launch. However, the development of CD20 targets has not been exhausted, and there are still 30% of patients who cannot benefit from "Meiluohua". To improve the prognosis of these high-risk patients, research and development still need to continue to advance, and humanity is once again on the front line of the fight against cancer. Pharmaceutical giants such as Eli Lilly, GlaxoSmithKline, and Xinji have all launched attacks on lymphoma at the same time. But how easy is it?
Since 2013, in the various indications of lymphoma, one drug candidate after another has been developed and entered the clinical phase I, phase II, phase III... Eventually, they all folded.
Eli Lilly's oral small molecule lymphoma drug Enzastaurin clinically failed; GlaxoSmithKline failed to make the anti-CD20 monoclonal antibody ofatumumab and sold it to Novartis a few years later; The immunomodulatory drug Revlimid of Singyl failed...
How many other drugs fail silently? It is no longer possible to count the exact figures.
The birth of each new drug has gone through twists and turns, not overnight, and each is cold and warm like a person drinking water. Faced with the common problems of mankind, even Roche, which successfully launched the first monoclonal antibody, has fallen into a long research and development bottleneck.
Pay homage to the classics in a way that goes beyond
In fact, after "Meiluohua", the industry has never stopped the pace of research and development.
In March 2016, Roche's new drug, human glycosylated type II CD20 monoclonal antibody otolizumab (common name: Jialuohua), was approved by the FDA for use in patients with follicular lymphoma. The upgraded version of the new drug, known as "Merova", was successfully approved in China in June 2021. Just half a year later, Jia Luohua was included in China's national medical insurance, filling the gap in the protection of follicular lymphoma in the medical insurance directory, which is almost the fastest record in the industry from approval to medical insurance.
Because of this, it is also known as "the new drug with the highest expectations of follicular lymphoma patients in China". Gu Hongfei, founder of the Lymphoma Home, told the Health Bureau: A few years ago, when otolizumab was doing research and development in China, he introduced some patients to participate in clinical research, and the patients achieved complete remission and have not recurred until now.
In the field of indolent lymphoma, "Jia Luohua" holds the baton of "Mei Luohua", and in the aggressive diffuse large B-cell lymphoma, the battle continues.
After countless failures, Roche's R&D team chose a new breakthrough point: challenging the 20-year classic treatment plan R-CHOP that they had established.
But whether this direction can go through, no one can give a definitive answer. Over the past 20 years, Roche's R&D team has conducted a large number of trials, and at least 11 drugs that have tried to challenge the R-CHOP program from different dimensions and different ideas have failed. Top R&D experts who are battling cancer head-on have lamented: "It's too difficult, it's failed many times." ”
This incident made the R&D team reflect on whether it was time to take a step back and explore the biological mechanisms of disease. In the CHOP regimen, the "O" stands for a drug called vincristine, which works well with chemotherapy but is neurotoxic, and patients feel numbness in their fingers, numbness in their toes, and pain. So they cleverly thought that if they could find a drug to replace vincristine, chop treatment options could be greatly improved. Is it possible to replace vincristine with a more precisely targeted drug?
Working in this direction, a CD79b ADC drug, Polatuzumab vedotin, was finally born. It's a game-breaking move in 20 years, setting new heights in the treatment of diffuse large B-cell lymphoma, and Roche pays tribute to the classic in a way that goes beyond — in December 2021, at the Annual Meeting of the American Blood Conference (ASH), Roche unveiled data from polariz, a clinical study of this innovative drug, and the results were particularly encouraging:
Vepotuzumab combined with R-CHP, or POLA-R-CHP, reduces the risk of disease progression or death by 27% compared to the R-CHOP regimen, with a better trend of benefit in asian populations and no unanticipated toxicity. This is the biggest breakthrough in the field of lymphoma treatment in two decades, and polarix has also won "LBA1" given the huge leap forward in this research.
Image source: LBA official website
The Health Bureau noted that roche has laid out a number of research and development pipelines in the field of blood diseases, including a number of new drugs for blood tumors and rare diseases, and is about to usher in a concentrated outbreak.
At the end of 2018, the new hemophilia drug amyclizumab (trade name "Shuyou Lile"),which was amazed by the industry, was approved in China, and it is still the only conventional preventive drug for hemophilia type A in the Chinese market that can simultaneously treat hemophilia with or without coagulation factor VIII inhibitors. In July 2021, Crovalimab, a C5 complement inhibitor used to treat paroxysmal sleep hemoglobinuria in rare blood diseases, was awarded breakthrough therapy certification by the State Food and Drug Administration. Recently, two CD20/CD3 dual anti-drugs Glofitamab and Mosunetuzumab, which also appeared in ASH, have also launched a number of clinical trials at home and abroad, of which Glofitamab has also been awarded a breakthrough therapy by the State Food and Drug Administration, which is expected to soon be a new treatment option for Chinese lymphoma patients.
"The research and development of the field of lymphoma has been very hot in recent years, in addition to Roche, we have also seen a variety of monoclonal antibodies, double antibodies, as well as PD-1, PD-L1 drugs, and CAR-T, which has been very hot, and now we have more and more new drugs available to our patients, which makes the treatment status of lymphoma change a lot," lamented Gu Hongfei, founder of the Lymphoma House.
The road to anti-cancer is long and arduous, and human efforts are far from reaching the end. Scientists have spanned more than half a century, from the initial nitrogen mustard, to later monoclonal antibodies, and now to ADC, double antibodies, lymphoma treatment options have been pointing to higher requirements.
Today, the therapeutic dilemmas of the seventies are long gone. The improvement of treatment technology has made more and more lymphoma patients become lucky, and I hope that the industry will have more transcendence to pay tribute to the classics, help patients to live, live longer, and live better, to love, to work, to live out of themselves.
Text | Zhang Ling
Operational | Twenty-thirteen
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