Before the pandemic, most people hadn’t heard of messenger RNA let alone could explain what it does. Today, mRNA has widespread recognition as part of the technology used in most of the Covid-19 vaccinations in the U.S. The pandemic isn’t over, but the success of the mRNA vaccines so far have created interest in leveraging the technology to subdue cancer.
The effort isn’t new.
In fact, Moderna and BioNTech, both of which are now manufacturing and supplying mRNA Covid vaccines globally, tested their technology in cancer long before the the first SARS-CoV-2 study. However, while the Covid clinical trials demonstrated safety and efficacy, as well as manufacturing scalability — removing many of the risks of this new vaccine technology — not all of that success will readily translate to cancer. That’s because cancer is such a complex disease.
Unlike the vaccines that protect against infectious diseases, cancer vaccines are therapeutic. But the concept is the same: Show the immune system an antigen, a protein it needs to recognize and respond to when it encounters a cell that expresses that protein. Messenger RNA brings advantages to the development of prophylactic and therapeutic vaccines. Once the target pathogen has been sequenced, mRNA can be quickly designed and produced. These genetic instructions tell a cell’s protein-making machinery how to make the target protein that will prompt the desired immune response.
Compared to the months-long development and production times for conventional vaccine technologies, the speedier process for making an mRNA vaccine is valuable for dealing with pandemics. The problem, said Daina Graybosch, a senior research analyst at SVB Leerink, is that these advantages don’t address the fundamental challenges that have stymied multiple cancer vaccine candidates.
“The unknown thing to solve in cancer is very different than the thing to solve for Covid,” she said. “In cancer, the hardest thing is which antigen and how many antigens do you put in your vaccine, and when do you give your vaccine, and with what other therapies.”
Learning from cancer vaccine failures
The history of cancer vaccine research is rife with clinical trial failures. In 2012, a cancer vaccine candidate from Germany-based Merck KGaA failed a lung cancer clinical trial. A GlaxoSmithKline cancer vaccine missed in melanoma in 2013, and then in lung cancer in 2014. In breast cancer, Galena Biopharma stopped work on its vaccine candidate in 2016 after an independent body concluded the study was unlikely to succeed. Brain cancer vaccines have suffered the same fate, first Celldex Therapeutics in 2016 followed by Agenus the following year.
The cancer vaccine clinical trial failures are due in part to the multiple mechanisms cancers use to elude the immune system, said Gur Roshwalb, a physician and partner at venture capital firm aMoon. Some cancers express proteins that tell immune cells not to attack. Tumors create microenvironments around themselves that turn off immune responses. Perhaps the biggest obstacle is selecting the right antigen. With the Covid vaccines, identifying the target antigen was relatively simple. Consensus formed quickly around the spike protein as the best target.
For cancer, there is no single spike protein equivalent. Most of the cancer vaccines that have failed were each developed to elicit an immune response to an individual antigen. While each of those antigen targets were found in abundance on cancer cells and not on healthy cells, that approach was not enough to succeed in clinical trials.
Targeting a single antigen leaves room for the cancer to find an alternate pathway and propagate. We’re witnessing a similar development with coronavirus variants. Sars-CoV2 is not consciously trying to survive, explained Don Diamond, a professor in the department of hematology and hematopoietic cell transplantation at City of Hope. But if enough variants propagate, eventually a variant develops that has a selective advantage enabling it to escape the vaccine or a therapy’s grasp, then spread. It’s already happened.
Last November, Eli Lilly’s bamlanivimab became the first antibody drug granted FDA emergency use authorization for treating Covid-19. Five months later, the agency revoked the authorization as new data showed the therapy, comprised of a single antibody, was not working against variants of the original virus. Similarly, in cancer, attacking from only one angle — as has been the case with the failed vaccine trials — could allow the cancer to take an alternate pathway that allows 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.]
So a successful cancer vaccine likely needs to target multiple antigens to prevent tumor escape, Graybosch, the SVB Leerink analyst, said. Or the vaccine can target an antigen that a cancer is addicted to for its survival. Some of these antigens might be good vaccine targets but some of them might not, she said.
Another challenge is the frequency of cancer mutations. Staying ahead of those mutations will be challenging for cancer vaccines, said Alexa Kimball, president and CEO of Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center and a professor of dermatology at Harvard Medical School. Even if research identifies promising tumor antigens, that’s no guarantee that the immune system recognizes them. Cancer cells are a patient’s own cells, so the immune system doesn’t always see them as foreign to the body.
“The trick of the work is finding out what about that cancer cell will be a target of interest for the immune system,” Kimball said.
New takes on tumor neoantigens
The search for the right antigens has led cancer vaccine developers to pursue neoantigens, which are antigens that form on tumors as they mutate. Neoantigens are unique to a patient’s tumor and personalized vaccines are made by sampling the tumor to find them.
Neon Therapeutics developed neoantigen cancer vaccines but advanced no further than early-stage clinical testing before running low on cash and being acquired by BioNTech last year for $67 million. Gritstone bio (formerly Gritstone Oncology) of Emeryville, California, is developing personalized and off-the-shelf neoantigen vaccines. The personalized neoantigen vaccine candidate is in Phase 2 testing in colorectal cancer. The company’s off-the-shelf program, which uses neoantigens that are shared across a subset of patients, is in the Phase 2 portion of a Phase 1/2 study in non-small cell lung cancer.
Moderna has two cancer vaccines that use mRNA to express tumor neoantigens intended to elicit an immune response. The personalized cancer vaccine, mRNA-4157, is made by sampling a patient’s tumor and sequencing it to identify the neoantigens. The company then designs the patient’s vaccine, which has mRNA that will encode up to 34 of those neoantigens. The other cancer vaccine, mRNA-5671, addresses the four most common KRAS mutations across cancers. Mutations in the KRAS gene are found in about 22% of cancers including colorectal, non-small cell lung and pancreatic cancers.
Both of Moderna’s mRNA cancer vaccines are being developed in partnership with Kenilworth, New Jersey-based Merck. The personalized vaccine is in Phase 2 testing in combination with the pharma giant’s cancer immunotherapy Keytruda. The KRAS-targeting vaccine is in Phase 1 testing evaluating by itself and in combination with the Merck immunotherapy.
The BioNTech pipeline lists eight mRNA cancer vaccine programs, five from the “FixVac” platform, which produces off-the-shelf vaccines from fixed combinations of cancer antigens. The lead vaccine candidate from this group is BNT111, which is designed to elicit an immune response to four antigens found in melanoma. Are these the right antigens? BioNTech is trying to make the case that they are. According to the company, sequencing data from 337 melanoma tumors detected at least one of the four antigens in 90% of the tumor samples. A Phase 2 study in advanced melanoma is evaluating BNT111 in combination with Libtayo, an immunotherapy marketed by Regeneron Pharmaceuticals and Sanofi.
BioNTech has one personalized mRNA cancer vaccine, BNT122, in development with Roche as a potential treatment for metastatic melanoma. This vaccine is made with up to 20 different neoantigens from the patient. A Phase 1 study is evaluating BNT122 in combination with Merck immunotherapy Keytruda.
If cancer vaccines work, they will almost certainly be used as part of combinations that bring a multi-pronged attack to cut off the ways cancers escape treatment, said Roshwalb, the physician and venture capitalist. He sees cancer vaccines potentially becoming part of drug cocktails that include one therapy that wakes up immune cells and perhaps a “checkpoint inhibitor,” a type of immunotherapy that blocks the proteins that keep T cells from attacking tumors.
When and where mRNA cancer vaccines fit
The composition of a drug combination isn’t the only consideration. The timing of the treatment is just as important. Graybosch and Kimball both say the ideal place for cancer vaccines is likely after surgery. Kimball explained that vaccines are best used when the number of cancer cells or the size of tumors is small — circumstances where initial treatment, such as surgery, eliminated tumors except for a few cells. Vaccines can then clean up what that initial treatment missed or they can be used to keep cancer from coming back, she said.
Similar thinking is shaping how companies test their vaccine candidates. BioNTech’s strategy for developing its personalized mRNA cancer vaccine for multiple types of solid tumors includes a planned Phase 2 clinical trial designed to enroll patients whose colorectal cancer has already been removed by surgery but is at high risk of returning. The study, expected to start later this year, will test the cancer vaccine as an adjuvant, a therapy given after the initial treatment to reduce the risk of such cancer recurrence.
Despite the promise of mRNA vaccines for treating cancer, the technology still has limitations. Diamond sees mRNA as a delivery mechanism rather than as a cancer solution. Tumors still have the immunosuppressive mechanisms that enable them to escape treatment, he said.
“It’s a way to be more efficient to get antigens to places where they could be valuable,” he said of mRNA. “But the same counterattacks still exist. And the mRNA is not going to relieve you of that.”
Aside from that, the instability of mRNA means that it doesn’t last long in the body. That feature isn’t a problem for infectious disease vaccines, such as the ones for Covid, but it’s not ideal for diseases where a longer-lasting effect is needed, Roshwalb said.
A growing number of startups have emerged to address mRNA’s limitations. Laronde, which like Moderna was formed by venture capital firm Flagship Pioneering, is developing “circular RNA” that engages with the cell’s protein-making machinery so that it makes protein continuously. In June, Strand Therapeutics unveiled its approach of programming mRNA so that it lasts longer in the body. Roshwalb notes that the vast majority of RNA in the human body is not mRNA. MiNA Therapeutics, an aMoon portfolio company, is developing drugs based on small activating RNA that turn on genes, like flicking a light switch, in order to boost production of a particular protein. MiNA is studying this approach as a way to affect the population of immune cells in the tumor microenvironment, potentially improving the efficacy of other cancer therapies.
How effective mRNA cancer vaccines being developed remains to be seen, and Roshwalb cautions against expecting anything close to the 90% plus efficacy posted by the Moderna and BioNTech Covid vaccines. Antigen selection is just one of the hurdles for mRNA cancer vaccines. These vaccines also need to elicit an appropriate immune response to cancer — enough to be effective but not so much that it triggers complications.
“It’s not just about getting the right proteins,” Roshwalb said. “It’s also about waking up the immune system.”
Image of mRNA by libre de droit, Getty Images