Preventing Cervical Cancer: The Development of HPV Vaccines

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Key Points

  • More than half a million women around the world are diagnosed with cervical cancer each year. Over half of them will die of the disease. Most of these cases and deaths occur in low- and middle-income countries.
  • Researchers supported by the National Cancer Institute (NCI) helped establish that human papilloma virus (HPV) is a major cause of cervical cancer, carried out studies to determine how HPV causes cancer, and developed the technology used to create the first HPV vaccines.
  • Research is under way to develop the next generation of vaccines, including one that could prevent 90 percent of cervical cancers worldwide.

Pathway to Discovery

As far back as the nineteenth century, the prevailing thinking was that a sexually transmitted agent causes cervical cancer. It took more than 100 years to identify the culprit. In the 1980s, researchers at the German Cancer Research Center found types of HPV in many cervical tumors. HPV’s role in cervical cancer seemed possible, as other viruses in the HPV family were already known to cause warts. Consequently, scientists—including many supported by NCI and in the NCI Intramural program—began to explore whether HPV could cause cancer; and if it did, scientists wanted to understand how the virus could cause cancer.

NCI achieves a key milestone. A team of NCI researchers led by Joe DiPaolo, M.D., and Jay Donniger, Ph.D., was among the first to show that DNA from HPV 16, the type of HPV found most often in cervical cancer cells, was able to cause cancer-like traits in cells grown in the lab. These researchers also showed that HPV 16 and mutations (cellular transformation) caused tumors to develop. This finding suggested that several mutations or alterations needed to take place in the cell at the same time to lead to cancer.

Nearly all cervical cancers are caused by HPV. In the early 1990s, two large epidemiological studies were conducted: one by NCI intramural researcher Mark Schiffman, M.D., and another by a group at the NCI-designated Albert Einstein Cancer Center. Using what was then a new DNA technology, these studies showed that a select group of HPV types is responsible for premalignant abnormalities found in Pap smear screening and for the development of most cervical cancers. Later studies showed that nearly all cervical cancers are caused by HPV.

NCI researchers Douglas Lowy, M.D., and John Schiller, Ph.D., pioneered discoveries that led to the development of the HPV vaccine. Credit: R. Baer

Is an HPV vaccine possible? Douglas Lowy, M.D., and John Schiller, Ph.D., in the NCI intramural research program, studied how HPV genes and proteins work. As the link between HPV and cervical cancer became stronger, these researchers and other scientists explored the possibility of developing a vaccine to prevent HPV infection.

One big hurdle was that HPV produces a local genital infection and all prior attempts to develop vaccines for this type of infection had failed. In addition, a vaccine needs to be very safe, and HPV contains genes (oncogenes) that can cause cancer to develop. Scientists also did not know how to produce large quantities of the outer shell of the virus in a way that would produce antibodies that may protect against other types of infection. Consequently, researchers turned to creating something that looked like HPV but did not include the potentially dangerous genes contained within HPV.

With NCI’s support, the impossible is made possible. In the early 1990s, two research groups—including one led by Drs. Lowy and Schiller, and another laboratory supported by NCI grants—independently discovered that the proteins that form the outer shell of HPV could form particles that closely resemble the original virus and create high levels of potentially protective antibodies but are not infectious because they lack the viral genes. These virus-like particles became the basis of several subsequent HPV vaccines, including Gardasil®, Cervarix®, and Gardasil® 9. All three vaccines are approved for the prevention of cervical cancer and other conditions caused by certain types of HPV.

When we started this work, there was no greater optimism for an HPV vaccine than there was for an HIV vaccine. In fact, there was skepticism that it could work at all.

Enhancing Cancer Prevention

Phase III clinical trials in young women found that Gardasil and Cervarix can prevent infection with HPV types targeted by the vaccine and prevent the development of precancerous lesions. The initial Gardasil study was so successful it was stopped early so that participants in the placebo group could also be offered the vaccine. The HPV Vaccine Trial in Costa Rica, a collaboration between investigators in Costa Rica and at NCI, demonstrated that two, and even a single, dose of Cervarix may provide a similar level of protection as the recommended three doses of the vaccine.

NCI is conducting a long-term follow-up study of women who participated in the Costa Rica trial to answer many more questions about vaccination with Cervarix, such as the extent and duration of protection.

Currently, more than 500,000 women around the world are diagnosed with cervical cancer each year and 275,000 will die of the disease. The vast majority of these cases and deaths occur in low- and middle-income countries. It has been estimated that widespread vaccination using currently available HPV vaccines could prevent more than two-thirds of cervical cancers.

Turning Discovery into Health

NCI-supported research helped establish HPV as a major cause of cervical cancer.

Although current HPV vaccines have an excellent safety record, getting people vaccinated has lagged in the United States. Research on strategies to disseminate the vaccine could help address this problem, as could efforts to enhance access to the vaccine in both developed and developing countries. Increasing awareness that the vaccine can prevent other cancers as well as cervical cancer may also help. Other research is looking at ways to simplify how the vaccines are administered to increase acceptance by the general population.

The ability of Gardasil to prevent genital warts, anal dysplasia, and anal cancer in males led to its approval by the FDA for men as well as women.  Further studies showed that two doses of the HPV vaccine can be as effective as three. The FDA, consequently, approved a two-dose regimen of Gardasil 9 for boys and girls ages 9 to 14 years old. The two-dose regimen could be very important for implementing vaccinations both in the United States and globally.

Research to Practice: NCI’s Role

NCI-supported researchers helped establish HPV as a major cause of cervical cancer, carried out studies to determine how HPV causes cancer, and developed the technology used to create the first HPV vaccines. NCI scientists also were involved in the initial trials of Cervarix and are contributing to ongoing clinical studies of the vaccine.

Source: www.cancer.gov

Immunotherapy: How the Immune System Fights Cancer

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Researchers are working to learn more about how the immune system works to fight cancer. Immunotherapy uses the body’s immune system to fight cancer. This animation explains three types of immunotherapy used to treat cancer: nonspecific immune stimulation, T-cell transfer therapy, and immune checkpoint inhibitors.

Pursuing a Cancer Prevention Vaccine

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For more than two decades, Olivera Finn has tirelessly pursued one goal in her research: to develop a vaccine to prevent cancer. She has had this goal since 1989, when her research team discovered the first tumor antigen recognized by a type of immune cell that can kill cancer cells. That antigen—an abnormal version of a protein called MUC1—is produced by the cells of more than 80% of cancer types, including cancers of the breast, pancreas, colon, lung, and prostate.

Although she started her research career as an organ transplant immunologist, the discovery of MUC1 was a pivotal point in Olivera’s career trajectory. “Once we discovered tumor antigens,” she said, “I never looked back.” Olivera received her first NCI grant in 1991 and has been funded ever since to study the biology of tumor antigens and develop them as targets for cancer prevention.

Cancer can take many years—even decades—to develop. Some cancers arise from precursor growths that can be detected by current screening methods. For example, colorectal polyps called advanced adenomas, which can be detected by colonoscopy, can progress to colorectal cancer. These adenomas can be removed surgically, but in many patients, new ones continue to develop and some will become malignant. Olivera’s lab found that the cells of advanced adenomas and the precursors of pancreatic, lung, and many other types of cancer all produce abnormal MUC1 protein.

The presence of abnormal MUC1 on premalignant growths may make it a good target for a vaccine that would prevent their progression to cancer or the development of new precursors. To test this idea, Olivera’s group conducted the first ever clinical trial of a cancer prevention vaccine based on a tumor antigen in healthy people without cancer who were at increased risk of developing the disease.

In the NCI-funded trial, reported in 2013, individuals with a history of advanced adenomas were given an MUC1 vaccine. The vaccine was shown to be safe and to elicit a strong immune response and a long-lasting immune memory. NCI is currently sponsoring a phase II trial testing whether the vaccine will prevent the regrowth of colorectal polyps.

Looking forward, Olivera envisions, “If you are in your 60s and your doctor discovers you are at high risk for cancer, the idea would be to vaccinate to boost the immune system’s ability to keep any abnormal cells in check instead of waiting to see if cancer develops.”

Olivera says that funding from NCI is critical for her research and for cancer prevention research in general. Cancer prevention research is complex, and translating laboratory discoveries into new ways to prevent cancer requires sustained investments over many years—investments that the private sector is often reluctant to make. But “building the evidence that vaccines are an effective way of controlling cancer will go a long way toward getting companies interested,” she said.

The field of cancer immunology has expanded dramatically and has led to immunotherapies for the treatment of advanced cancers as well as vaccines against some viruses that cause cancer. Boosting the immune system to prevent cancers that are not caused by viruses may now be within reach. “The opportunities are amazing,” she added.

 

What are Cancer Vaccines?

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Approved Cancer.Net Editorial Board, 08/2020

Vaccines are medicines that help the body fight disease. They can train the immune system to find and destroy harmful germs and cells. There are many vaccines that you receive throughout your life to prevent common illnesses. There are also vaccines for cancer. There are vaccines that prevent cancer and vaccines that treat cancer.

Are there vaccines that prevent cancer?

There are vaccines that can prevent healthy people from getting certain cancers caused by viruses. Like vaccines for the chicken pox or the flu, these vaccines protect the body from these viruses. This type of vaccine will only work if a person gets the vaccine before they are infected with the virus.

There are 2 types of vaccines that prevent cancer approved by the U.S. Food and Drug Administration (FDA):

HPV vaccine. The vaccine protects against the human papillomavirus (HPV). If this virus stays in the body for a long time, it can cause some types of cancer. The FDA has approved HPV vaccines to prevent:

HPV can also cause other cancers the FDA has not approved the vaccine for, such as oral cancer.

Hepatitis B vaccine. This vaccine protects against the hepatitis B virus (HBV). This virus can cause liver cancer.

Are there vaccines that treat cancer?

There are vaccines that treat existing cancer, called treatment vaccines or therapeutic vaccines. These vaccines are a type of cancer treatment called immunotherapy. They work to boost the body’s immune system to fight cancer. Doctors give treatment vaccines to people who already have cancer. Different treatment vaccines work in different ways. They can:

  • Keep the cancer from coming back
  • Destroy any cancer cells still in the body after treatments end
  • Stop a tumor from growing or spreading

How do cancer treatment vaccines work?

Antigens, found on the surface of cells, are substances the body thinks are harmful. The immune system attacks the antigens and, in most cases, gets rid of them. This leaves the immune system with a “memory” that helps it fight those antigens in the future.

Cancer treatment vaccines boost the immune system’s ability to find and destroy antigens. Often, cancer cells have certain molecules called cancer-specific antigens on their surface that healthy cells do not have. When a vaccine gives these molecules to a person, the molecules act as antigens. They tell the immune system to find and destroy cancer cells that have these molecules on their surface.

Some cancer vaccines are personalized. This means they are made for just 1 person. This type of vaccine is produced from samples of the person’s tumor that are removed during surgery. Other cancer vaccines are not personalized and target certain cancer antigens that are not specific to an individual person. Doctors give these vaccines to people whose tumors have those antigens on the surface of the tumor cells.

Most cancer vaccines are only offered through clinical trials, which are research studies that use volunteers. In 2010, the FDA approved sipuleucel-T (Provenge) for people with metastatic prostate cancer, which is prostate cancer that has spread. Sipuleucel-T is tailored to each person through a series of steps:

  • White blood cells are removed from the person’s blood. White blood cells help the body fight infection and disease.
  • The white blood cells are altered in a laboratory to target prostate cancer cells.
  • Next, the doctor puts the altered cells back into the person through a vein. This is similar to a blood transfusion. These modified cells teach the immune system to find and destroy prostate cancer cells.

Another vaccine uses a weakened bacteria called Bacillus Calmette-Guérin (BCG) that is injected into the body. This weakened bacteria activates the immune system to treat early-stage bladder cancer.

What are the challenges of using treatment vaccines?

Making treatment vaccines that work is a challenge because:

Cancer cells suppress the immune system. This is how cancer is able to begin and grow in the first place. Researchers are using adjuvants in vaccines to try to fix this problem. An adjuvant is a substance added to a vaccine to improve the body’s immune response.

Cancer cells start from a person’s own healthy cells. As a result, the cancer cells may not “look” harmful to the immune system. The immune system may ignore the cells instead of finding and fighting them.

Larger or more advanced tumors are hard to get rid of using only a vaccine. This is 1 reason why doctors often give a cancer vaccine along with other treatment.

People who are sick or older can have weak immune systems. Their bodies may not be able to produce a strong immune response after they receive a vaccine. That limits how well a vaccine works. Also, some cancer treatments may weaken a person’s immune system. This limits how well the body can respond to a vaccine.

For these reasons, some researchers think cancer treatment vaccines may work better for smaller tumors or cancer in its early stages.

Vaccines and clinical trials

Clinical trials are key to learning more about both cancer prevention vaccines and cancer treatment vaccines. Researchers are testing vaccines for many types of cancer, including:

Bladder cancer. Researchers are testing how well a vaccine made from a virus altered with the HER2 antigen works. These antigens or molecules live on the surface of some bladder cancer tumors. The virus may help teach the immune system to find and destroy these tumor cells. Researchers also want to know which works better: standard bladder cancer treatment or standard treatment with a vaccine.

Brain tumors. There are many studies testing treatment vaccines aimed at certain molecules on the surface of brain tumor cells. Some focus on newly found brain cancer. Others focus on cancer that has come back, or recurred. Many of the studies include children and teens.

Breast cancer. Many studies are testing treatment vaccines for breast cancer, given alone or with other treatments. Other researchers are working to get vaccines that prevent breast cancer into clinical trials.

Cervical cancer. As explained above, the FDA approved HPV vaccines that prevent cervical cancer. Research continues on vaccines that help treat each stage of cervical cancer.

Colorectal cancer. Researchers are making treatment vaccines that tell the body to attack cells with antigens thought to cause colorectal cancer. These antigens include carcinoembryonic antigen (CEA), MUC1, guanylyl cyclase C, and NY-ESO-1.

Kidney cancer. Researchers are testing many cancer vaccines to treat kidney cancer. They are also testing vaccines to prevent kidney cancer in its later stages from coming back.

Leukemia. Studies are looking at treatment vaccines for various types of leukemia, such as acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Some are meant to help other treatments, such as a bone marrow/stem cell transplant, work better. Other vaccines made from a person’s cancer cells and other cells may help the immune system destroy the cancer.

Lung cancer. Lung cancer treatment vaccines in clinical trials target antigens.

Melanoma. Researchers are testing many melanoma vaccines, given alone or with other treatments. Destroyed melanoma cells and antigens in the vaccines tell the immune system to destroy other melanoma cells in the body.

Myeloma. There are many clinical trials looking at vaccines for people with multiple myeloma who are near remission. This means doctors can no longer find the cancer in the body and there are no symptoms. Researchers are also testing vaccines in people with smoldering myeloma or who need to have an autologous bone marrow/stem cell transplant.

Pancreatic cancer. Researchers are working on many treatment vaccines designed to boost the immune system’s response to pancreatic cancer cells. The vaccine may be given as the only treatment or along with another treatment.

Prostate cancer. As noted above, sipuleucel-T is a vaccine that doctors can use to treat people with prostate cancer that has spread. Now studies are looking to see if the vaccine can help people with prostate cancer at earlier stages.

Learn more about the latest research for specific cancers in this website’s guides and finding a clinical trial.

Questions to ask your health care team

If you want to learn more about joining a cancer treatment vaccine clinical trial, talk with your health care team. You may want to ask these questions:

  • Is there a clinical trial testing a vaccine for my type and stage of cancer?
  • Where is the clinical trial located?
  • What is the vaccine and how does it work?
  • How is the vaccine made? Will I need blood cells or tumor tissue removed to make the vaccine? How will you remove it?
  • How will I receive the vaccine and how often?
  • How long will I need the vaccine?
  • What side effects could occur?
  • Can I receive the vaccine with other treatments such as radiation therapy or chemotherapy?
  • What are the other treatment options for this cancer?

Related Resources

Getting Treatment in a Clinical Trial

Making Decisions About Cancer Treatment

Clinical Trials

Podcast: Should People With Cancer Be Tested for Hepatitis B?

More Information

National Cancer Institute: Cancer Treatment Vaccines