Coloured scanning electron micrograph (SEM) of two T lymphocyte cells attached to a cancer cell

Cancer vaccines are showing promise. Here’s how they work.

The immediate goal is to create vaccines that destroy cancer cells—but some scientists are also testing vaccines that might prevent someone from developing cancer.

A colored scanning electron micrograph of two T lymphocyte cells (yellow) attached to a cancer cell (green). T lymphocytes are a type of white blood cell and a component of the body's immune system. They recognize a specific target—an antigen—on the surface of the cancer cell and bind to it. Once a T-cell has bound to the cancer cell it can signal for other immune cells to destroy it. 
Micrograph by STEVE GSCHMEISSNER, SCIENCE PHOTO LIBRARY

Typically, vaccines help protect us against diseases. But cancer vaccines are different; they are potential therapies for treating people who already have cancer. These treatments have been years in the making, and failures have been frequent, but they’re now starting to show some promise.

In the last decade, technological innovations like genome sequencing have allowed scientists to take a closer look at tumor cells and their genetic abnormalities. This is helping them design vaccines aimed at much more specific targets. At the same time, we’ve been learning a lot more about the immune system and how it recognizes and destroys a patient’s tumor, says cellular immunologist Stephen Schoenberger at the La Jolla Institute for Immunology in San Diego.

Cancer vaccine research is still in the nascent stages, says Nina Bhardwaj, a hematology and medical oncology expert at the Icahn School of Medicine at Mount Sinai in New York. But early results from clinical trials testing dozens of vaccine candidates against a variety of cancers look encouraging, she says.

The goal is to roll out vaccines that destroy cancer cells, but some scientists are also testing vaccines that might one day prevent a high-risk individual from developing cancer.

What are cancer vaccines?

The purpose of all vaccines, be it a cancer vaccine or COVID-19 vaccine, is to educate the immune system and provide a preview of the target that needs to be identified and destroyed to keep the body safe. The COVID-19 vaccine teaches the immune system what the SARS-CoV-2 virus looks like so when the pathogen infects, immune cells can quickly locate the virus and kill it. Similarly, a cancer vaccine educates immune cells about what a tumor cell “looks like,” enabling them to seek and destroy these cancer cells.

The ability of a cancer vaccine to teach the immune system is what distinguishes it from other immunotherapies that utilize therapeutic agents such as cytokine proteins and antibodies and include strategies like genetically engineering a patient’s immune cells to fight cancer.

Experts says that cancer vaccines can potentially destroy cancer cells that might have survived other treatments, stop the tumor from growing or spreading, or stop the cancer from coming back.

Some therapeutic cancer vaccines rely on removing immune cells called dendritic cells from a patient’s blood sample and exposing them in the laboratory to the key proteins obtained from the individual’s cancer cells. These educated cells are then returned to the patient with the expectation they will stimulate and train other immune cells, such as T cells, to detect and destroy the cancer.

T cells can do one of the most amazing tricks in biology, says medical oncologist Christopher Klebanoff at New York’s Memorial Sloan Kettering Cancer Center. They carry a receptor that can recognize and bind to proteins present on tumor cell surfaces—as a lock fits a key. Once bound, the T-cells use mechanical force to punch a hole through the tumor cell and destroy it, he says.

But “vaccines haven’t been very good at generating the quality and quantity of T cells necessary to eliminate large tumors,” Bhardwaj saysIt’s ideal to vaccinate when the tumor is small, she says. 

To boost the power of the vaccine, researchers often combine it with drugs that enhance this antitumor immune response.

Vaccine-makers now are increasingly relying on mRNA technology—also used to create COVID-19 vaccines—to instruct dendritic cells in a patient’s body to produce the tumor-specific proteins or peptides that will generate an immune response.

A few vaccines are preventative as they teach the body to kill a cancer-causing viruses like hepatitis B and human papillomavirus, thus averting an infection that could otherwise lead to a tumor.

How do scientists create cancer vaccines?

All cancer-treating vaccines rely on proteins, called tumor-associated antigens—a molecule that triggers an immune response when it’s either more plentiful on the surface of cancer cells compared to healthy ones, or exists in an abnormal or mutated form. Once T cells “see” these antigens they recognize the cells as cancerous and kill them.

Cancer biologists identify these tumor antigens with sophisticated sequencing technology that spots specific differences between the DNA or RNA of a healthy cell versus a cancer cell. The trick is to understand which mutations will generate a T cell response and would make a good target for a vaccine, Schoenberger says.

His research group selects antigens based on a patient’s response to the cancer. By studying the T cells in their blood samples, “we’re looking at what the patient’s own immune system has selected among the tumor-expressed mutations to target,” Schoenberger says. He identifies antigens that are unique to an individual’s tumor cells and uses a combination of tumor-specific antigens from different patients to create vaccines. Other researchers look for antigens that are shared between individuals who have a certain cancer, or between different cancer types.

Vaccines designed to target molecules that are overproduced by cancer cells but also present in smaller amounts in healthy cells tend to have limitations and may not initiate an effective immune response. “That’s been a huge hurdle,” says cancer immunologist Lisa Butterfield at the University of California, San Francisco. There’s also the danger of inducing autoimmunity, in which the immune system ends up attacking healthy cells, resulting in bodily disorders that are hard to treat. More efforts are now focused on finding target molecules called neoantigens that are specific to tumors.

Are there approved vaccines to treat cancer and how they do work?

In 2010, the U.S. Food and Drug Administration approved the first therapeutic cancer vaccine, called Sipuleucel-T, to treat advanced prostate cancer. Its target is an antigen called prostatic acid phosphatase. It’s present in normal prostate cells but is found in higher amounts in cancerous ones. Clinical trials showed patients vaccinated with Sipuleucel-T lived about four months longer, although their tumors remained the same size.

Other vaccines that have been approved against viruses like hepatitis B and human papillomavirus are also considered cancer vaccines because they prevent viral infections that could one day lead to liver, cervical, head, and neck cancers.

These preventative vaccines work by generating antibodies against the virus, and to the best of our knowledge, not a very effective T cell response, Klebanoff says. “That’s why they can’t be used as a therapy against cancer.”

What cancer vaccines are in the pipeline?

Scientists are testing dozens of cancer vaccines, often in combination with other immunotherapies. They’re targeting various types of cancer, including skin, breast, bladder, prostate, and pancreatic cancer.

Last week, vaccine-maker Moderna announced that its candidate mRNA vaccine against stage three or four melanoma showed a 44 percent reduction in risks of skin cancer recurrence or death among patients who received both the vaccine and a Merck drug called Keytruda, which boosts the immune response against cancer cells, compared to those who took only Keytruda. Moderna’s personalized mRNA vaccine trains the immune system to produce T cells against 34 cancer-specific antigens. Although the results of this phase two clinical trial are yet to be peer-reviewed, the company, along with Merck, is planning a larger phase three trial in 2023 to test the vaccine’s safety and efficacy.

Cancer immunologist Olivera Finn at the University of Pittsburg is testing a preventative vaccine that can be given at a pre-cancer stage, when an individual develops benign growths called polyps—which are not dangerous but can turn malignant—inside their colon. The vaccine targets an abnormal form of a protein called MUC1 produced by some non-malignant colon polyp cells. It led to a 38 percent reduction in recurrence within three years of vaccinating nearly 50 individuals with advanced polyps. “If you don’t get a new polyp, you’re not going to be at an increased risk of a colon cancer,” Finn says.

An important next step for scientists is to figure out why some people respond better to the vaccines than others and how long they’ll be protected. Until then, the hope is to see more vaccine candidates progress to phase three randomized clinical trials where their safety and effectiveness will be evaluated in a large group of patients.

What challenges do scientists foresee?

Despite the renewed excitement in developing and testing cancer vaccines, given technological advances, some scientists like Klebanoff remain skeptical. He wonders if the vaccines will ever be potent enough to cause tumor shrinkage in a way that is clinically meaningful and whether alternatives like engineering a patient’s T cells—so called CAR-T cell therapy—so they can better recognize tumor cells will be a more effective strategy. His research group uses the latter approach. But he remains eager to see what the data from ongoing vaccine clinical trials reveals.

Since therapeutic vaccines are often tested in patients with advanced cancer who have had their tumor surgically removed and have been through chemotherapy or radiation, their immune systems are really beat up, Schoenberger says. It’s likely that the vaccines may not perform as well at this late stage of disease. We’ll need to find the patients and the specific clinical settings in which cancer vaccines are most effective, he says.

Cancer vaccines are still in the early phases of testing and refining, Butterfield cautions. There’s a lot of work to be done, both on the preventative and therapeutic vaccines front.

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