Before the pandemic, most people had never heard of messenger RNA, let alone explain its role. Today, mRNA is widely recognized as part of most Covid-19 vaccination technologies in the United States. The pandemic is not over yet, but the success of mRNA vaccines so far has aroused interest in using this technology to suppress cancer.
This effort is not new.
In fact, Moderna and BioNTech both manufacture and supply mRNA Covid vaccines worldwide, and have tested their technology in cancer before the first SARS-CoV-2 study. However, although Covid clinical trials have proven safety and effectiveness, as well as the scalability of manufacturing—eliminating many of the risks of this new vaccine technology—not all of these successes can easily translate into cancer. That’s because cancer is a very complex disease.
Unlike vaccines that prevent infectious diseases, cancer vaccines are therapeutic. But the concept is the same: to show the immune system an antigen, a protein that needs to recognize and respond when it encounters a cell expressing that protein. Messenger RNA brings advantages to the development of preventive and therapeutic vaccines. Once the target pathogen has been sequenced, mRNA can be quickly designed and produced. These genetic instructions tell the cell’s protein-making machinery how to make the target protein to promote the desired immune response.
Compared with the development and production time of several months for traditional vaccine technology, the faster manufacturing process of mRNA vaccines is valuable for dealing with epidemics. According to Daina Graybosch, senior research analyst at SVB Leerink, the problem is that these advantages do not solve the fundamental challenges that hinder multiple cancer vaccine candidates.
“The unknown problem solved in cancer is very different from the problem solved for Covid,” she said. “In cancer, the most difficult thing is to add which and how many antigens to the vaccine, when to vaccinate, and what other therapies to use.”
Learn from cancer vaccine failure
The history of cancer vaccine research is full of failures in clinical trials. In 2012, a cancer vaccine candidate from Merck KGaA, Germany Failure Lung cancer clinical trials.GlaxoSmithKline Cancer Vaccine Missed melanoma In 2013, then in Lung cancer in 2014. In breast cancer, Galena Biopharma stop working In 2016, after an independent agency concluded that the study was unlikely to succeed, the company conducted research on its vaccine candidates. The brain cancer vaccine also suffered the same fate, The first Celldex therapy 2016 followed Belong to The following year.
Gur Roshwalb, a doctor and partner at the venture capital firm aMoon, said that part of the reason for the failure of cancer vaccine clinical trials is the multiple mechanisms that cancer uses to evade the immune system. Some cancers express proteins that tell immune cells not to attack. The tumor creates a microenvironment around itself, shutting off the immune response. Perhaps the biggest obstacle is choosing the right antigen. With the Covid vaccine, it is relatively simple to identify the target antigen. A consensus was quickly formed around the spike protein as the best target.
For cancer, there is no single spike protein equivalent. Most failed cancer vaccines were developed to trigger an immune response to a single antigen. Although each of these antigen targets are found on cancer cells rather than healthy cells, this approach is not enough to be successful in clinical trials.
Targeting a single antigen leaves room for cancer to find alternative ways and spread. We are witnessing similar developments in variants of the coronavirus. Don Diamond, professor of the Department of Hematology and Hematopoietic Cell Transplantation in the City of Hope, explained that Sars-CoV2 did not consciously try to survive. However, if enough variants are spread, a variant with selective advantages will eventually be produced, allowing it to escape the control of vaccines or therapies, and then spread. It has already happened.
In November last year, Eli Lilly’s bamlanivimab became the first antibody drug approved by the FDA Emergency use authorization Used to treat Covid-19.Five months later, the agency Revoke The authorization of the new data shows that this therapy consisting of a single antibody is not effective against variants of the original virus. Similarly, in cancer, attacking from only one angle — like a failed vaccine trial — can allow cancer to take another approach and allow it to thrive, Diamond said.[Lilly has another Covid-19 antibody drug comprised of two antibodies, as does Regeneron Pharmaceuticals, combinations designed to be more effective than one antibody alone.]
SVB Leerink analyst Graybosch said that a successful cancer vaccine may therefore need to target multiple antigens to prevent tumor escape. Or the vaccine could target cancers that are addictive to their survival. She said that some of these antigens may be good vaccine targets, but some of them may not be.
Another challenge is the frequency of cancer mutations. Alexa Kimball, president and CEO of Beth Israel Deaconess Medical Center Harvard Medical School and professor of dermatology at Harvard Medical School, said that staying ahead of these mutations will be a challenge for cancer vaccines. Even if studies identify promising tumor antigens, there is no guarantee that the immune system will recognize them. Cancer cells are the patient’s own cells, so the immune system does not always treat them as foreign bodies in the body.
“The trick of this work is to find out that cancer cells will become targets of interest to the immune system,” Kimball said.
New perspectives on tumor neoantigens
The search for the right antigen has prompted cancer vaccine developers to look for new antigens, which are antigens that are formed on tumors when they mutate. Neoantigens are unique to patient tumors, and personalized vaccines are made by sampling tumors to find them.
Neon Therapeutics developed a neoantigen cancer vaccine, but only conducted early clinical testing before cash was insufficient and troubled Acquired by BioNTech for US$67 million last year. Gravel Creature (Previous Gritstone Oncology) In Emeryville, California, is developing personalized and ready-made neoantigen vaccines. The personalized neoantigen vaccine candidate is in Phase 2 testing for colorectal cancer. The company’s ready-made plan uses neoantigens shared among some patients and is currently in the phase 2 part of the phase 1/2 study of non-small cell lung cancer.
Moderna has two cancer vaccines that use mRNA to express tumor neoantigens designed to trigger an immune response. The personalized cancer vaccine mRNA-4157 is made by sampling the patient’s tumor and sequencing it to identify new antigens. The company then designed a vaccine for the patient, which has mRNAs that can encode up to 34 new antigens. Another cancer vaccine, mRNA-5671, addresses the four most common KRAS mutations in cancer. KRAS gene mutations are found in approximately 22% of cancers, including colorectal cancer, non-small cell lung cancer, and pancreatic cancer.
Moderna’s two mRNA cancer vaccines were developed in cooperation with Merck, which is headquartered in New Jersey. The personalized vaccine is being tested in the second phase in conjunction with Keytruda, the cancer immunotherapy of the pharmaceutical giant. The KRAS targeted vaccine is in the first phase of testing, to be evaluated separately and used in combination with Merck’s immunotherapy.
The BioNTech pipeline lists eight mRNA cancer vaccine projects, five of which are from the “FixVac” platform, which uses a fixed combination of cancer antigens to produce ready-made vaccines. The main vaccine candidate for this group is BNT111, which is designed to trigger an immune response to the four antigens found in melanoma. Are these the correct antigens? BioNTech is trying to prove that they are. According to the company, sequencing data from 337 melanoma tumors detected at least one of the four antigens in 90% of tumor samples.A sort of The second phase of research In advanced melanoma, the combination of BNT111 and Libtayo, an immunotherapy marketed by Regeneron Pharmaceuticals and Sanofi, is being evaluated.
BioNTech has a personalized mRNA cancer vaccine BNT122, which is being developed in collaboration with Roche as a potential treatment for metastatic melanoma. This vaccine is made of up to 20 different neoantigens from patients. A phase 1 study is evaluating the combination of BNT122 and Merck’s immunotherapy Keytruda.
Roshwalb, a doctor and venture capitalist, said that if cancer vaccines are effective, they will almost certainly be used as part of a portfolio, bringing a multi-pronged attack that cuts off cancer’s avenues for evading treatment. He believes that cancer vaccines may become part of a drug cocktail, including a therapy that wakes up immune cells, and a “checkpoint inhibitor,” an immunotherapy that blocks proteins that prevent T cells from attacking tumors.
When and where mRNA cancer vaccines are suitable
The composition of the drug combination is not the only consideration. The timing of treatment is equally important. Both Graybosch and Kimball said that the ideal place for a cancer vaccine may be after surgery. Kimball explained that when the number of cancer cells or the size of the tumor is small, it is best to use a vaccine-in this case, the initial treatment (such as surgery) eliminates the tumor except for a few cells. She said that the vaccine can then remove the missing parts of the initial treatment, or it can be used to prevent the cancer from recurring.
Similar ideas are shaping the way companies test their vaccine candidates. BioNTech’s strategy to develop personalized mRNA cancer vaccines for multiple types of solid tumors includes a planned phase 2 clinical trial aimed at recruiting patients who have undergone surgery to remove colorectal cancer but are at high risk of recurrence. The study is expected to begin later this year and will test the cancer vaccine as an adjuvant, which is a treatment performed after the initial treatment to reduce the risk of recurrence of this type of cancer.
Although mRNA vaccines are expected to be used to treat cancer, the technology still has limitations. Diamond sees mRNA as a delivery mechanism, not a cancer solution. He said tumors still have immunosuppressive mechanisms that allow them to evade treatment.
“This is a more effective way to bring antigens to where they might be valuable,” he said of mRNA. “But the same counterattack still exists. And mRNA won’t free you from this.”
In addition, the instability of mRNA means that it will not last long in the body. Roshwalb said that this function is not a problem for infectious disease vaccines (such as Covid vaccines), but it is not ideal for diseases that require longer-lasting effects.
More and more start-up companies have emerged to address the limitations of mRNA.Like Moderna, Laronde, founded by the venture capital firm Flagship Pioneering, is developing “Circular RNA” It is combined with the cell’s protein manufacturing machine to continuously produce protein. In June, Strand Therapeutics announces its mRNA programming method So that it lasts longer in the body. Roshwalb pointed out that the vast majority of RNA in the human body is not mRNA. aMoon portfolio company Mina Therapeutics is developing a The small activating RNA that turns on the gene, It’s like pressing a light switch to promote the production of specific proteins. MiNA is studying this method as a way to influence the immune cell population in the tumor microenvironment, which may improve the efficacy of other cancer therapies.
The effectiveness of the mRNA cancer vaccines being developed remains to be seen. Roshwalb warns against expecting the release of Moderna and BioNTech Covid vaccines to be close to 90% or more effective. Antigen selection is only one of the obstacles of mRNA cancer vaccines. These vaccines also need to elicit an appropriate immune response to cancer-effective enough without causing complications.
“It’s not just getting the right protein,” Roshwalb said. “This is also to wake up the immune system.”
Royalty-free, mRNA image courtesy of Getty Images
