New progress has been made in the treatment of cancer, is the mRNA vaccine really playing?

What does it mean for the first mRNA tumor vaccine to be recognized as a "breakthrough therapy"?

　　China News Weekly reporter/Peng Danni

　　Published in the 1082nd issue of "China News Weekly" magazine on March 6, 2023

　　In the near future, humans may use vaccines to treat cancer, an ancient and intractable disease.

On February 22, 2023, Moderna and Merck announced that their tumor neoantigen mRNA vaccine mRNA-4157, combined with PD-1 antibody in the adjuvant treatment of high-risk melanoma, has received breakthrough therapy from the US Food and Drug Administration (FDA) This is the world's first mRNA tumor vaccine to receive this certification.

　　In January, the UK government announced a partnership with German company BioNTech to test mRNA vaccine technology for cancer and other diseases.

The project, which aims to start trials of personalized mRNA therapies in more than 10,000 UK patients by 2030, will begin as early as this autumn.

Moderna and BioNTech happen to be two biotechnology companies that have become famous for their mRNA COVID-19 vaccines during the COVID-19 pandemic.

　　At present, there are dozens of clinical trials related to mRNA tumor vaccines around the world.

In addition to involving melanoma, it also includes pancreatic cancer, colorectal cancer, etc. Some trials are used in combination with other tumor immune drugs, but none of them has been officially approved by the FDA.

　　"Tumor vaccines are finally making progress." The media, including Bloomberg, wrote.

Kong Na, a researcher at Zhejiang University School of Medicine, said in an interview with China News Weekly, "This is a milestone advancement in the field of cancer immunotherapy." Moderna's breakthrough means that clinical research and regulatory approval of this type of therapy can be accelerated , and further confirmed the potential of mRNA tumor vaccines as a tool for personalized cancer therapy.

　　Many interviewees pointed out that when more funds come in, tumor vaccines are expected to become another star track in the field of tumor treatment after PD-1.

However, this medical technology still has many scientific and industrial challenges before it can be used.

Making cancer vaccines is Moderna's "old business"

　　In the 1970s, Hungarian scientist Katalin Kariko pioneered early mRNA research. From then to December 14, 2020, when the first mRNA vaccine was approved in the United States, more than 40 years have passed.

　　For more than 30 years, researchers in the field of cancer disease have been developing treatments known as personalized vaccines.

In fact, harnessing the magic of mRNA to fight cancer has been a long, low-key, bumpy journey.

Before the new crown vaccine, the main research and development focus of many companies, including Moderna, was the cancer vaccine based on the mRNA platform.

　　Its core principle is very simple: the world's most powerful drug factory may be in our body.

mRNA (messenger ribonucleic acid) is essentially a code, like a computer's 0s and 1s, that tells cells which proteins to make.

With engineered mRNA, it is theoretically possible to control this process and create any desired protein—such as an antibody for immunization, an enzyme to reverse a rare disease, or a growth factor to repair damaged heart tissue.

　　Kong Na told "China News Weekly" that since the 1990s, scientists have begun to try to use mRNA technology for disease treatment, and their important attempts have two directions: mRNA immunotherapy and protein replacement therapy.

The former includes preventive vaccines and therapeutic vaccines, and the latter restores the function of a certain protein that is missing or mutated by the body itself through the normal target protein encoded by the body.

　　In contrast, so far, the development of mRNA vaccines has progressed faster.

Kong Na explained that this is mainly because the dose required for protein replacement therapy is several orders of magnitude higher than that of vaccines, which is a great challenge for industrial synthesis and cost control.

Under such a large dose, what side effects will be brought to the human body also needs further research; protein replacement therapy requires intravenous injection, and the requirements for the delivery system are much higher than those for mRNA vaccine products.

　　In 2008, Uger Shaheen and his wife, who were engaged in immunotherapy research, saw the huge potential of mRNA and established a new company BioNTech in Germany, which is the abbreviation of "New Biopharmaceutical Technology" in English.

In 2010, Robert Lange, a professor of biomedical engineering at the Massachusetts Institute of Technology, Nuba Afeyan, the founder of Cambridge venture capital company Flagship, and others established Moderna, a company that combines Modified (modified) and RNA. new word.

　　Before turning to the new crown vaccine, Moderna had conducted more than a decade of research on cancer and infectious disease vaccines.

In people's conception, vaccines are generally used for the prevention of infectious diseases: by producing and inoculating the characteristic proteins of pathogens or processed pathogens, the immune system can recognize and remember them in advance to achieve preventive effects.

People are confused, why would a vaccine be used as a treatment?

And why is it a tumor?

　　There are some cancers caused by oncogenic viruses, such as cervical cancer caused by human papillomavirus (HPV), which have preventive vaccines.

But many more tumors are not due to foreign pathogens, including viruses or bacteria.

　　A tumor is a group of cells that grow uncontrollably after a genetic mutation has occurred in human cells.

With the deepening understanding of tumors, scientists have discovered that after cancer cells mutate, they will produce uniquely expressed neoantigens.

So, naturally, an idea similar to that used to develop flu vaccines is also being used against cancer.

　　"Tumor patients are very heterogeneous." Kong Na said, just as everyone's genes are different, each cancer patient's tumor mutation is also completely different. If drugs can be personalized for mutations, precise treatment can be truly realized .

　　In Moderna's latest study, scientists encoded synthetic mRNA molecules containing up to 34 neoantigens designed using bioinformatics algorithms based on the unique DNA sequence mutation signature of each patient's tumor.

When the vaccine is injected into the body, the new antigen sequence carried by the mRNA molecule will be translated into protein, and presented through the antigen in the body, attracting T cells to attack cancer cells to play a role.

　　What Moderna announced this time is the results of a phase II clinical trial.

A total of 157 patients were enrolled in the trial. Compared with PD-1 drug pembrolizumab (referred to as "K" drug) monotherapy, after cancer vaccine and K drug were used in combination, after complete tumor resection, III and IV Among patients with advanced melanoma, the combination therapy reduced the risk of recurrence or death by 44%.

In terms of safety, treatment-related serious adverse events occurred in 14.4% of patients receiving combination therapy and in 10% of patients receiving K alone.

　　Melanoma is a type of skin cancer.

In the past few decades, the incidence of melanoma has been increasing. In 2020, there will be 325,000 newly diagnosed melanoma patients worldwide. The 5-year survival rates of patients with stage III and IV melanoma are 60.3% and 16.2%, respectively.

　　After the results of the mRNA-4157 phase II phase were announced in December 2022, Francis Collins, former director of the National Institutes of Health, said in an interview with the Washington Post: "Using mRNA technology to develop cancer vaccines may be a major post-epidemic challenge." One of medical advances." Cancer vaccines have a lot of potential, he says, but they don't really work.

Now with mRNA, this can be done much faster.

　　However, according to US industry media reports, from obtaining tumor samples to treating patients, the personalized vaccine still takes about 45 days to make, and the two companies continue to try to shorten this process.

"A New Era of Tumor Immunotherapy"

　　Tumor neoantigen vaccines had a wave of enthusiasm 8 to 10 years ago, but the previous research and development basically failed, and several companies around the world went bankrupt. Ren Dean Ding Sheng pointed out in an interview with China News Weekly that this technical route is not as simple as everyone imagined.

　　Pang Yuxuan, vice president of Cochuang Weiye Investment and an investor in the field of biomedicine, told China News Weekly that domestic attention to tumor neoantigen vaccines has experienced two major climaxes, namely 2014 and 2017.

At two points in time, the early positive data of companies such as Neon in the United States and BioNTech in Germany were published in high-level journals, which aroused the attention of the domestic capital market on tumor neoantigens. Especially around 2017~2018, overseas companies have more Clinical data has prompted the birth of a number of domestic companies dedicated to the development of tumor vaccines.

　　In July 2017, "Nature" published two papers in succession.

In the U.S. and Germany, two research groups report similar medical advances: Teams from the Dana-Farber Cancer Institute at Harvard University in the U.S. and BioNTech, both report surprising tumor vaccines they saw in small clinical trials Effect.

　　A US research team tested a personalized tumor vaccine on six melanoma patients.

According to the mutated gene of each patient, they produced a vaccine containing 20 protein fragments. During the 2-year follow-up period, 4 patients did not relapse.

The study by a team led by BioNTech founder Ug Shaheen included 13 melanoma patients. The vaccine used contained RNA encoding 10 mutant proteins in each patient; 8 of them had no visible tumors when they were injected with the vaccine. One year later remained tumor-free.

　　"We are about to enter a new era of tumor immunotherapy." At that time, Ug Shaheen said with confidence.

The scientist who specializes in tumor immunity and tumor genomics has led BioNTech to make a big bet on mRNA cancer therapy for many years.

　　Cheng Xudong, founder of Zhongsheng Kangyuan, a biotechnology company in the field of tumor vaccines, analyzed China News Weekly that this field has not achieved some qualitative breakthroughs and leaps until recent years, first of all thanks to the progress of basic research.

The development of modern immunology, tumor genomics and other sciences has made the selection of tumor antigens from blind and qualitative to precise and quantitative, which has also brought about the discovery of tumor neoantigens; The improvement of technologies such as next-generation sequencing and the support of bioinformatics tools have supported the rapid development of tumor neoantigen vaccines.

　　The research and development of PD-1/PD-L1, CAR-T and other drugs has brought tumor treatment into the era of immunotherapy, and has also deepened the understanding of tumor immunology by scholars in the field.

Robert Meehan, Moderna's senior director of clinical development, noted that there are many synergies between immunotherapy and mRNA cancer vaccine research.

Tumor vaccines build on the success of PD-1 drugs, a process that expands scientists' fundamental understanding of biology.

　　This time, mRNA-4157 was chosen to be used in conjunction with the PD-1 drug "K drug" in tumor immunotherapy. This broad-spectrum anticancer drug has now been approved for at least 16 different tumor treatments.

Many scientists pointed out that the combination of the two can better allow the immune system to respond to tumors, further amplify the effect of tumor immunotherapy, and solve problems such as drug resistance of anti-PD drugs.

　　Moderna and Merck plan to start Phase III clinical trials this year and quickly expand this combination therapy to other tumor types, including non-small cell lung cancer.

Stephen Bancel, CEO of Moderna, said in an interview with the media at the end of last year that he would explore the effect of the tumor vaccine in other cancers. All should be useful."

　　In addition to mRNA technology, there are other paths in the therapeutic tumor vaccine map, including peptide vaccines, DC vaccines, etc., and their underlying principles are similar.

In tumor therapy, traditional chemotherapy, radiotherapy, targeted drug therapy, and immunotherapy for cancer do not completely replace each other. There are currently many more effective combination therapies. In the end, human beings are likely to use multiple combinations to overcome the disease. Cancer, said Ding Sheng.

After the influx of capital and confidence

　　However, many interviewed scholars pointed out that the progress of this clinical trial must also be viewed objectively. From a scientific point of view, the data themselves are not particularly amazing.

On the one hand, melanoma itself is a cancer that is more likely to respond to immunotherapy. Unlike other tumors, melanoma is a notoriously highly mutated cancer, and it is also called a "hot tumor" in the industry. Therefore, Immunosuppressant drugs such as PD-1 are also more effective in treating melanoma.

　　In 2017, when tumor vaccines reported positive data one after another, "Nature" magazine wrote that personalized tumor vaccines still face many challenges.

Vaccines will work better if they target genetic mutations in multiple tumors, because researchers have more choices when designing vaccines, but other tumor cells have relatively few genetic mutations, making it more difficult to design vaccines.

　　In the past, the research and development of mRNA tumor vaccines has seldom touched on the treatment of tumor types with severe immunosuppression, such as pancreatic cancer and glioblastoma. In the face of these "harder bones", how effective mRNA technology is remains to be seen. See the results of clinical trials.

　　On the other hand, Cheng Xudong pointed out that the immunogenicity of the tumor vaccine is also relatively weak. Among the 20 patients grouped, the number of antigen-specific T cells activated by the vaccine was only three times higher than that of the test group using PD-1 alone. , is not particularly obvious.

"I think it will be difficult for mRNA therapeutic vaccines to make a huge breakthrough in the short term, and it will take a while."

　　Obtaining the breakthrough therapy certification does not mean that the effectiveness of the therapy has been approved by the FDA. Ding Sheng emphasized that it is only an encouragement for those very cutting-edge and promising therapies, which will be supported and approved in clinical trials in the future Aspects give some fast track.

But at the same time, there are many drugs that have been certified as "breakthrough therapies" and then declared to have failed clinical trials.

Pang Yuxuan also said that in recent years, the FDA has revoked more than a dozen such identifications.

　　In 2018, two years after returning to China, Cheng Xudong founded Zhongsheng Kangyuan Biotechnology Company.

In his opinion, in addition to the specific clinical trial data, the latest progress of Moderna's personalized tumor vaccine has far-reaching significance for the development of the field.

　　Cheng Xudong analyzed that the success of the new crown vaccine in the new crown pandemic has given Moderna enough financial resources to re-support the progress of its R&D pipeline - the company's revenue in 2022 is already close to 20 billion US dollars, the progress of the industry leader It will drive the continuous development of this field; in addition, after the verification of the new crown epidemic, the mRNA technology platform has not only received more attention and capital influx, but also the large-scale use of the new crown vaccine in the market has also driven the maturity of the entire industry. It will also promote the progress of tumor vaccines.

　　Cheng Xudong believes that "tumor vaccines are likely to become another star track in the field of cancer treatment after PD-1." The mRNA technology platform company Si Microbiology also announced that the clinical research of its mRNA tumor vaccine in the treatment of postoperative patients with liver cancer was launched at Zhongshan Hospital affiliated to Fudan University.

In academic journals, relevant clinical trial results are also being released continuously.

　　Ding Sheng pointed out that after the good news of the clinical research of companies such as Moderna, it will definitely stimulate some capital and companies that have given up and are waiting to join in, and even bring a certain R&D bubble.

　　Another big challenge is that the cost of personalizing treatment based on K-drug, which itself is priced at about $185,000 per year, can be prohibitively high.

Although companies such as Moderna have not disclosed the price of their tumor vaccines.

However, some scientists pointed out in 2020 that it may cost $100,000 to make such a vaccine for everyone.

　　"mRNA technology is a large platform technology that can develop various treatments for different indications, but at the same time, mRNA is only one of various drug forms. Will it have better clinical efficacy than other technology platforms? Follow-up clinical trials to carry out rigorous demonstration." Pang Yuxuan, an investor in the field of biomedicine, said.

　　(Intern Li Jinjin also contributed to this article)

　　"China News Weekly" Issue 8, 2023

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