Cancer research was a quiet hero in the fight against COVID-19. We are now acquainted with mRNA vaccines—the technology behind both the BioNTech/Pfizer and Moderna vaccines—which enabled scientists to test and manufacture COVID-19 vaccines in record time. One of the reasons mRNA vaccines were so readily deployed for COVID-19 is because cancer researchers were already studying them, along with similar modalities like DNA vaccines, for use in cancer.
While vaccines are known for their use in infectious disease, they are another potential tool in the expanding arsenal of immunotherapies. Tumors are supposed to be eliminated by the immune system; they disrupt surrounding tissues, and many generate thousands of abnormal and mutated proteins that should constantly trigger immune alarm bells. But cancer evolves to grow without interference by hiding from immune detection or blocking immune activation. Most immune-modulating drugs on the market should release the tumor-induced brakes on immunity, but they are not always enough, especially in contexts where the tumor is still “invisible.”
Vaccines help the immune system both detect and attack things it didn’t see before. In the case of COVID-19, the vaccines show your body what parts of the COVID virus look like, generating a portion of the coronavirus known as the “spike.” Cancer researchers are looking for the equivalent of the spike protein for tumors to render them visible and train the immune system to identify and eradicate cancer cells.
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Vaccines have three potential uses in cancer: treating patients with existing tumors, helping patients who are at a high risk of cancer recurrence, and preventing cancer from occurring at all. There are more than 50 active clinical trials for vaccines in breast cancer—most falling into the first two categories—but their effectiveness is still unknown as the studies are in the earliest stages.
Harnessing cancer’s complexity
Vaccines expose our bodies to antigens: molecules our immune system recognizes as foreign objects that need to be eliminated from the body. In the case of the COVID-19 vaccine, the antigen was the aforementioned spike protein, one small component of the virus. The coronavirus causing this year’s pandemic has about 30 such proteins to choose from as antigens. Unlike this virus, tumors can have thousands of potential antigens. And cancer vaccines face the same challenge that all therapies in oncology encounter: Tumors are complex, unstable, and capable of resistance. They could evolve to alter or stop creating a specific antigen to avoid detection (somewhat like a COVID variant).
The good news is that cancer researchers are not restricted to one antigen. In fact, using several might help prevent the tumors from developing resistance to the vaccines.
Off-the-shelf breast cancer vaccines
When designing a vaccine, some researchers incorporate a handful of antigens found in many patient tumors. Known as tumor-associated antigens (TAAs), they are selected because cancer cells produce them at high levels. Ultimately, TAAs serve as helpful beacons that effectively announce to the immune system, “This is a tumor.”
BCRF investigators are running a few exciting clinical studies for TAA vaccines. Dr. Mary L. Disis is leading early-stage trials with vaccines for both HER2-negative and HER2-positive patients at risk of disease recurrence. BCRF also supports a trial helmed by Drs. Robert Vonderheide and Susan Domchek. In one arm of the trial, the vaccine will be given to patients diagnosed with breast cancer who currently have no evidence of disease. In the other, the vaccine will be administered to people with BRCA1/2 mutations who are otherwise healthy. If the vaccine is successful in the latter population and after further study, it would be the first-ever cancer prevention vaccine for individuals with a BRCA1/2 mutation.
Using TAAs is helpful for designing one vaccine that can be manufactured in large batches and distributed to a wide population of patients as a one-size-fits-many approach. One of the main challenges is ensuring that the TAAs generate the desired immune response. Our immune system is carefully calibrated to ensure that it does not attack our body, also known as immune tolerance. Autoimmune diseases result when this calibration goes awry. Some TAAs may be found, albeit at low levels, in healthy tissues. As a result, tumor associated antigens might not generate an immune response at all, because the immune system perceives them as off limits. On the other hand, if the TAAs bypass our immune tolerance mechanisms, immune cells may target other parts of the body, which can result in toxicity and safety issues. It is a careful tightrope to walk.
Personalized approaches
Neoantigens—the other main tactic for designing cancer vaccines—are specific to tumor cells and generated mainly by changes to the DNA. Tumors are genetically unstable; as they grow, some acquire thousands of mutations and genetic aberrations, and a commensurate number of neoantigens. Compared to TAAs, neoantigens are more likely to seem abnormal to the immune system.
Some neoantigens show up repeatedly across patient tumors, often because they are functionally important for tumor progression and are so beneficial that many tumors evolve to develop them. These are known as shared antigens, and several researchers are working to integrate them into vaccines.
Within each patient’s tumor, there may be tens, hundreds, or thousands of neoantigens that are entirely unique. These can be used to generate personalized cancer vaccines. To do so, patients provide a sample of tumor tissue and normal tissue from the same organ for comparison. After sequencing and computational analysis, researchers select the neoantigens most likely to induce an immune response. The selected neoantigens will be used for a custom-made vaccine, and this is where new technologies like mRNA and DNA vaccines shine, because they are amenable to personalization and can be generated relatively quickly.
There are a handful of active clinical trials in breast cancer for neoantigen vaccines. Preliminary trials with personalized neoantigen vaccines in other cancers reveal that they are safe, feasible, and stimulate the immune system. Further study is required to confirm the same for breast cancer, and eventually to test if they affect disease progression.
While we await the results of these trials, we also must consider some of the limitations of personalized neoantigen vaccines. These include the cost to manufacture individual vaccines, and timing, as the process can take months. For patients with aggressive, metastatic disease, these months matter.
We are in the early days of cancer vaccine development—cancer is far more complex than any single virus, and warp speed is not in the cards. But as we saw with this research field’s contributions to resolving a global pandemic, the beauty of scientific discovery is that advancements in one field can expedite the work of another. Research will help us take on the world’s deadliest diseases and needs our continued investment to sustain innovation.
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