Rita Rubin, MA
Malignant tumors are sneaky. They tend to fly under the immune system’s radar because, unlike invaders such as viruses or bacteria, cancer cells arise from normal cells, so they bear many of the same familiar molecules on their surface.
Once tumors are established, they become even more adept at hiding out from the immune system. They might cloak themselves in proteins to block immune cells from entering them or undergo genetic changes to further reduce the chance that disease-fighting cells will notice anything is amiss.
In approximately 80% of human cancers, “the immune system maybe cannot see cancers as nonself,” making immunotherapy ineffective, said Vinod Balachandran, MD, a hepatopancreatobiliary surgeon at Memorial Sloan Kettering Cancer Center who runs a laboratory in the hospital’s Immuno-Oncology Program.
But scientists who are developing cancer vaccines aim to change that scenario.
Already, immunizations against human papillomavirus and hepatitis B protect against cervical and liver cancers, respectively. But unlike those shots or vaccinations against infectious diseases, the goal of new experimental cancer vaccines is treatment, not prevention.
“Not all vaccines are the same,” Catherine Wu, MD, leader of the Division of Stem Cell Transplantation and Cellular Therapies at the Dana-Farber Cancer Institute, noted in March at the most recent meeting of the National Cancer Advisory Board, which advises the National Cancer Institute. Wu, cochair of a new Cancer Vaccine Roadmap Advisory Committee, coauthored a review article on cancer vaccines published the week before the advisory board meeting.
Prophylactic vaccines against infectious diseases generate antibodies for the most part, whereas therapeutic cancer vaccines increase the breadth and diversity of the tumor-specific T-cell response, explained Wu, codeveloper of an investigational individualized vaccine that boosted the immune response against melanoma in a trial of 10 patients.
One of the most promising cancer vaccine platforms is messenger RNA, or mRNA, the same technology used in the Moderna and Pfizer-BioNTech COVID-19 vaccines. Delivered in lipid particles, the mRNA in these COVID-19 vaccines trains cells to make the spike protein found on the surface of SARS-CoV-2, thus priming the immune system to generate antibodies and other disease-fighting cells when it encounters the virus.
Cancer mRNA vaccines also train cells to make proteins designed to stimulate an immune response. In this case, the proteins are neoantigens, which are found only in tumor cells, not healthy cells.
With mRNA vaccines that induce these proteins, “you can make really strong immune responses that may impact clinical outcomes,” Balachandran said.
The US Food and Drug Administration has not yet approved any mRNA vaccine to treat cancer, but small trials of them against a variety of malignancies, including melanoma, pancreatic cancer, and glioblastoma, have been encouraging. Even so, whether the US government will continue to invest in this research isn’t clear, and some experts fear that vaccine hesitancy born of misinformation could spill over to these promising therapies.
What’s tricky in the quest to develop therapeutic cancer vaccines is that no single tumor features the same set of neoantigens as another, even if they are the same type of malignancy.
As Wu told the cancer advisory board, neoantigens “are exquisitely tumor specific,” and tumor heterogeneity and tumor evolution are 2 of the biggest obstacles toward developing effective cancer therapies.
“This is a massive challenge for any vaccine because it’s against the original tumor, and we know those tumors are going to evolve,” said pediatric neurosurgeon Elias Sayour, MD, PhD, principal investigator of the RNA Engineering Laboratory within the Preston A. Wells, Jr. Center for Brain Tumor Therapy at the University of Florida. “But this is also why I tell people that mRNA is the perfect tool.”
Sayour pointed to the mRNA COVID-19 vaccines as an example. “People in the community said it was fruitless to make a vaccine against the coronavirus because it’s changing,” he explained. But mRNA technology, which researchers began investigating for cancer immunotherapy back in the 1990s, is easy to make and can be quickly adjusted if necessary.
The creation of mRNA cancer vaccines begins with the resection of a patient’s tumor. Scientists then use next-generation sequencing to identify neoantigens on the tumor that would make suitable targets for a personalized mRNA vaccine, which is then administered in multiple doses, sometimes with another immunotherapy treatment.
Much of the research on mRNA cancer vaccines has focused on melanoma because, compared with other tumors, it has a high mutational burden, which has been linked with tumor immunogenicity and response to immunotherapy such as checkpoint inhibitors.
“Melanoma was the first cancer where immunotherapy was shown to work,” Balachandran said. “It has been the poster child of a cancer where you can harness the immune system to fight it.”
Researchers have enrolled 1100 patients with high-risk melanoma into an international phase 3 trial testing a combination of Merck’s immunotherapy drug pembrolizumab (Keytruda) and Moderna’s intismeran autogene, an experimental individualized neoantigen therapy.
Median 5-year follow-up data from the combination treatment’s phase 2b trial, which included 167 patients, showed that it cut the risk of recurrence or death in half compared with pembrolizumab alone, the companies announced in January.
The firms plan to present details of the 5-year follow-up data at an upcoming major oncology meeting, said Moderna Vice President Michelle Brown, MD, PhD, oncology portfolio lead. Researchers have already published their 3-year findings and their primary analysis, both of which showed a significant benefit of the combination therapy over the pembrolizumab monotherapy.
To create the personalized neoantigen therapy, samples of trial participants’ tumors and blood are sent to a central laboratory for sequencing. The goal is to deliver the treatment to patients within 6 weeks of their samples arriving at the laboratory, Brown said. Patients receive a total of 9 intramuscular injections of their intismeran autogene therapy, 1 shot every 3 weeks.
Moderna is conducting a total of 10 trials with intismeran autogene against such malignancies as high-risk, nonmuscle invasive bladder cancer, in which it is combined with the standard treatment, bacillus Calmette-Guérin, or BCG.
“We do think that this therapy can be used for a wide variety of patients,” Brown said of intismeran autogene.
Moderna intentionally does not refer to its treatment as a vaccine, Brown noted. “Yes, it is a vaccine-like mechanism—training and activating the immune system to recognize foreign antigens on a tumor.”
But calling it a vaccine is likely to leave the public confused, she said. “The key here is that vaccine in a lot of folks’ minds is prevention,” Brown explained. “This is an active treatment for somebody who has been diagnosed with cancer.”
