“We’ve been living with the promise of cancer vaccines for, probably, 100 years. Until now, all we had were studies that were inconclusive, but this one is conclusive.” Immunologist Antoni Ribas of the University of California Los Angeles (UCLA), who is part of the scientific committee for the Moderna and MSD (Merck in the U.S. and Canada) melanoma vaccine trial that made headlines last week, says he learned of the announcement when a reporter called him to ask about the results. Ribas says that despite his proximity to the project, he was not shown concrete data on the vaccine’s benefit. “With announcements of this magnitude, which can have a big impact on share prices, they do not give anyone the data in advance and they must notify everyone at the same time,” he explains.
Days after the announcement, Moderna shares have more than doubled in value, representing tens of billions in market capitalization, while MSD, a much larger company, has seen its share price rise by about 10%. Investors are betting that the results could change cancer treatment.
The trial that has shaken up the outlook for vaccines was conducted on melanoma patients who had undergone surgery but were at risk of relapse. The trial included 1,137 patients; one-third received the immunotherapy drug pembrolizumab (Keytruda) and the experimental group — the other two-thirds — also received an mRNA vaccine designed to train the immune system to detect the specific mutations of each patient’s cancer. Although detailed data from this study are not yet available, in an earlier, smaller trial the combined treatment reduced the risk of relapse or death by 49% compared with immunotherapy alone.
Although people talk about cancer in the singular, oncologists stress that it is not one disease but hundreds. Part of the vaccine’s success has to do with the type of cancer treated. “For the immune system to destroy them, it has to recognize cancer cells as different from normal cells. In melanoma that is feasible because most changes are induced by sun exposure, and ultraviolet radiation generates mutations in the tumor’s DNA that are not present in healthy cells,” Ribas explains. “That means vaccines can be useful in other cancers such as lung or bladder, for which Moderna is also developing this vaccine and which are also induced by a carcinogen — tobacco — but it is hard to think it will work in other cancers such as colon, prostate, or breast, when there is not the same number of distinct mutations between the tumor and normal tissues; if there is not enough difference, you cannot make the vaccine.”
The melanoma vaccine has been developed with the same technology as the Covid vaccines. Messenger RNA is a molecule that carries instructions from the cell nucleus’s DNA to produce all kinds of proteins we need to live. Scientists have managed to harness that capability and use it to create proteins to train the immune system. In the case of the Covid virus, the spike protein was introduced to identify it. In cancer, the process involves taking a biopsy, sequencing the genome to detect mutations, using prediction algorithms to select which mutations serve as targets, and manufacturing the corresponding mRNA.
But the problem posed by cancer is much harder. Viruses are external invaders and the immune system is designed to detect them. It is enough to show a small part of the virus to the body so it learns to recognize and destroy it. Cancer, by contrast, arises from our own cells. It is a distorted, mutated version of our normal self. That is why the immune system often has difficulty recognizing tumors as threats. Moreover, cancer changes continuously, between patients and within each individual. A universal vaccine like the one developed for Covid is impossible and, as Ribas illustrates, this type of treatment is “as if we gave a different Covid vaccine to each person.”
For decades, researchers have been accumulating knowledge until they began to see success. As an international team of oncologists explained in a review published in Nature Medicine, many older vaccines targeted common proteins that, although expressed at higher levels in tumors, were also found in healthy tissues. Because the immune system was accustomed to them, the response was weak.
Another major mistake was testing them on patients with very advanced cancers. When a tumor has been attacking a person for years, it has developed mechanisms to disable the body’s defenses, and it is not possible to use the vaccine to train an immune system that has already been almost completely dismantled.
Luis Paz-Ares, head of the Medical Oncology Department at the 12 de Octubre University Hospital in Madrid, says the trial “was done in resected stage 2 to 4 melanomas, high risk,” and that “if efficacy is confirmed, it would be logical to extend the strategy to earlier stages, such as stage 1, because vaccines tend to be more effective the earlier the disease and the more intact the patient’s immune system.”
Juan José Lasarte, co-director of the Immunology and Immunotherapy program at Cima (Center for Applied Medical Research) at the University of Navarra, says the difference in the Moderna and MSD trial is “the specific patients chosen.” “These are patients from whom the tumor has been removed, but because some cells remain that the surgeon cannot excise, there is a risk of relapse, and there, with a small tumor burden, vaccination can control the subsequent growth of the few remaining cells,” he notes. “When there is a large primary tumor or metastases, vaccination has not shown much efficacy.”
Finally, another problem was that vaccines were used alone. It is now known that a vaccine can generate immune cells capable of recognizing a tumor’s specific mutations, but those cells become exhausted if not combined with other drugs that release the immune system brakes that tumor cells activate to defend themselves. That is the case with the treatment announced last week, which combines a vaccine with pembrolizumab, a drug that removes inhibitory signals on T cells so they can attack the cancer.
MSD and Moderna already have eight more trials underway using the same personalized vaccine technology in other cancers such as lung, bladder, and kidney, and many other companies have trials focused on other tumors. There are more than 100 mRNA-based technologies alone, though their chances of becoming treatments vary. In this regard, Ribas criticizes that “sometimes things that may be interesting from a scientific point of view are presented as major results, but not for the general population as effective treatments.”
Technologies like mRNA are promising, and the same concept could appear useful across many fields. But the experience with vaccines warns that the complexity of cancer and the immune system often overwhelms those concepts. Moreover, these treatments can cost more than €100,000 (over $115,000), which makes widespread application across all tumor types difficult, at least for now, even if they work.
Lasarte raises the need to keep exploring other, more affordable alternatives. “We have, for example, oncolytic viruses: you inject the virus into the tumor, the virus causes tumor cell death and that releases those neoantigens without needing to know which they are, inflammation is produced and that triggers what we call in situ vaccination. You do not need sequencing information; you simply provoke the tumor’s immune activation naturally,” he says.
In the popular imagination, one of the biggest items of news humanity could receive is a cure for cancer, and that is why the term vaccine can be confusing. A vaccine eradicated smallpox, but it is unlikely to do so for cancer. It is an enemy that looks a lot like ourselves, with many faces and many masks, but ground is being gained through partial battles.
Last June, for example, results were presented from a trial of a drug targeting the KRAS protein, responsible for aggressive growth in pancreatic cancer and other tumors. Patients who received the drug doubled their survival time. Targeting the effects of that mutated gene was something scientists had begun to view as unattainable, and it is likely to transform the treatment of many types of cancer. Vaccines are now also beginning to show results.
Paz-Ares recalls that since he began his career, almost 40 years ago, five-year survival for cancer patients has doubled. “It has gone from the low-thirties percent to more than 60% today, and that is because, successively, advances have emerged that have helped subgroups of patients with specific subgroups of tumors,” he says. “I do not expect that we will have a penicillin for cancer, because cancer is many diseases, and we will have to assign a different penicillin, a different strategy, to each one. All these results are complementary and will help fewer patients suffer from cancer and more patients live longer and live better.”
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