Cancer vaccines, while not a new idea, have gained momentum in recent years, leading to an increase in research efforts.
“Although evidence that our immune system can eliminate tumors was already observed in the 1890s, tumor immunology has been a minor research field because it was believed that our immune system cannot attack self-derived cancer cells,” explained Takemasa Tsuji, PhD, Assistant Professor of Oncology at Roswell Park Cancer Institute, Buffalo, N.Y.
“Since the seminal discovery in 1991 that one of the human tumor antigens, called MAGE-A1, is recognized by white blood cells, many other immunogenic tumor antigens have been identified and cancer vaccines targeting such molecularly defined tumor antigens are being actively tested today.”
What Are Cancer Vaccines?
Similar to traditional vaccines, cancer vaccinations target infectious agents that cause or contribute to the development of cancer, according to the National Cancer Institute (NCI).
“Cancer vaccines are composed of three components: immunogen, which stimulates immune cells; delivery system, which targets immunogens to a specific immune cell called ‘antigen-presenting cells’; and adjuvant which potentiate immune reaction,” noted Tsuji. “Cancer vaccines have greatly evolved in all three components based on our understanding of the immune system.
“For example, earlier cancer vaccines injected a synthetic peptide, a short fragment from a tumor antigen protein that only stimulates defined T-cell population, which is reactive to this peptide, but most current cancer vaccines use the whole tumor protein to stimulate broad T-cell population,” he continued. “Additionally, the recent discovery of human toll-like receptors and their corresponding ligands was rapidly incorporated into the cancer vaccine formulation to enhance the vaccine-induced immune responses.”
Another recent finding revealed that cancer cells overexpress immune-suppressive molecules, such as PD-L1 to escape attack by immune cells, according to Tsuji, and the antibodies that block these molecules were found to be effective to treat cancer patients.
“Such therapies called ‘checkpoint blockades’ are considered an additional component of cancer vaccines to further enhance immune cell-mediated tumor destruction,” he explained. “It was also found that cancer cells epigenetically silence the molecules for recognition by immune cells. To re-express these molecules, several recent reports included epigenetic modulators in the vaccine. Cancer vaccines have been and will continue to evolve with our understanding of the immune system and tumors.”
Cancer vaccines can be divided into two categories: preventive (prophylactic) vaccines, which target infectious agents that cause or contribute to the development of cancer, and treatment (therapeutic) vaccines, a form of immunotherapy that treats an existing cancer by strengthening the body's natural immune response against the cancer.
Types of Vaccine
Currently, there are two types of preventative cancer vaccines available in the U.S. for human papillomavirus (HPV) and hepatitis B virus (HBV), as well as one treatment vaccine for metastatic prostate cancer.
HPV Vaccines: The FDA has approved three vaccines to prevent HPV infection: Gardasil, Gardasil 9, and Cervarix, according to NCI. Persistent HPV infections can lead to cervical cancer; anal cancer; oropharyngeal cancer; and vaginal, vulvar, and penile cancers.
“Cancer prevention vaccines work to stimulate the immune system and to act against some antigens that could lead to cancer, which is the science behind the HPV vaccination,” said Maurie Markman, MD, President of Medicine and Science, Cancer Treatment Centers of America. “The available HPV vaccines are nearly 100 percent effective in preventing the required precursor, which is the incorporation of the HPV genetic material into the lining of the cervix and the lining of the oropharynx or neck.
“It is important to remember that we are not treating cancer,” he emphasized. “What we are doing is preventing the virus from incorporating itself into the DNA of the normal cervix in females, or the normal oral track lining cells in both men and women.
“By vaccinating the population, it stimulates that normal immune system so that if it comes into contact with the HPV virus it can eliminate it and ensure that it doesn't become persistent. Given the overwhelming evidence supporting the effectiveness of HPV vaccines, I cannot overstate the importance of young women and men receiving the vaccination prior to sexual activity.”
When it comes to preventative vaccines, Markman emphasizes the importance of making sure the public and health care professionals beyond oncology are aware of their significance.
“We have overwhelming evidence of the benefits of the HPV vaccine and yet we can't figure out how to get these young individuals vaccinated and there are reasons for that,” he explained. “The bottom line is [that] it is not going to be the cancer provider who does the vaccinations. We are talking about people who don't have cancer, so how do we translate the overwhelming benefit that is going to occur later in life that is quite evident to the cancer doctors who see the complications of the cancer, but they have nothing to do with the actual vaccination strategy.
“So we need to figure out how to take the data and generate a strategy that is going to be used in the public health setting by totally different doctors,” Markman continued. “I would argue that is a very important part of the conversation.”
HBV Vaccines: The chronic liver failure associated with HBV can lead to liver cancer. In 1981, the FDA approved the original HBV vaccine, which is also the first cancer preventative vaccine to be successfully developed, according to NCI. Since then the FDA has approved multiple vaccinations that prevent HBV infection. Two vaccines protect solely against HBV and can be used for all ages: Engerix-B and Recombivax HB.
Other vaccines, according to NCI, can be used for HBV as well as other infections. For example, Twinrix protects against HBV and hepatitis A virus, and Pediarix guards against HBV, poliovirus, and the bacteria that cause diphtheria, tetanus, and pertussis.
Metastatic Prostate Cancer Vaccine: Sipuleucel-T (Provenge) was approved by the FDA in April 2010 and is the first cancer treatment vaccine. It is approved for the treatment of metastatic prostate cancer in some patient populations.
Designed to stimulate an immune response to prostatic acid phosphatase (PAP), an antigen that is found on most prostate cancer cells, sipuleucel-T increased the survival of men with a certain type of metastatic prostate cancer by about 4 months in clinical trials (N Engl J Med 2010;363:411-22).
This vaccine is customized to each individual patient. It is developed by isolating immune system cells called dendritic cells from a patient's blood through a procedure called leukapheresis, according to NCI. These cells are cultured together with the protein PAP-GM-CSF. Typically, patients then receive three treatments, usually 2 weeks apart, with each round of treatment requiring the same process.
Researchers around the world are focused on the development and use of cancer vaccines, and are at various stages in the research process. A number of trials were highlighted at the 2016 ASCO Annual Meeting, including a phase II trial of the WT1 analog peptide vaccine in adults with acute myeloid leukemia (Abstract 7005). A late clinical-stage cancer immunotherapy being developed to target hematologic cancers and solid tumors, including AML, MPM, multiple myeloma, ovarian cancer, and multiple other cancers, the WT1 vaccine has proved to be well-tolerated and linked to prolonged survival. A phase III trial of the vaccine in AML patients is expected to begin later this year.
A phase II trial is currently underway for the treatment of triple negative breast cancer with the cancer vaccine TPIV 200. The first patient is being treated at the University of Maryland, one of eight participating sites. This trial evaluates the safety and immunogenicity of two doses of the folate receptor alpha (FR) peptide vaccine mixed with GM-CSF as a vaccine adjuvant, with or without an immune priming with cyclophosphamide, as a consolidation therapy after neoadjuvant or adjuvant treatment of patients with stage 2b-3 triple negative breast cancer (NCT02593227).
“Except for the few FDA-approved cancer vaccines, most are still in a developmental stage as investigational drugs in clinical trials,” noted Tsuji. “We are currently learning from these trials to optimize treatment regimens, vaccine formulations, and biomarkers for responses.”
Treatment Vaccine Challenges
While researchers continue to work diligently to optimize the development and use of cancer treatment vaccines, it has proved challenging.
“Treatment vaccines remain a work in progress,” said Markman. “In my specialty, gynecological disease, there have been two companies that have tried very hard to create vaccines for ovarian cancer and both randomized trials have failed, which emphasizes the difficulty and complexity of cancer and why the development of treatment vaccines will be a lot tougher than researchers had hoped.”
According to NCI, treatment vaccines must achieve two goals: 1) they must stimulate specific immune responses against the correct target and 2) the immune responses must be powerful enough to overcome the barriers that cancer cells use to protect themselves from attack by killer T cells.
“One of the challenges in the development of effective cancer vaccines is tumor heterogeneity” explained Tsuji. “For example, even for a single type of tumor, expression profile of tumor antigens is different in each patient, and in many cases, tumor antigens are heterogeneously expressed within a tumor region. Therefore, multiple vaccine targets should be identified and developed to treat broad cancer patients.
“In addition, each patient has different immunological status so that the immunological and clinical responses to cancer vaccines are highly variable. So, it would be important to identify biomarkers that predict effects of cancer vaccines as a monotherapy or combination therapy,” he continued. “To provide the most promising cancer vaccine in a personalized way, we still need to learn from patients through extensive research. As mentioned before, cancer vaccines have evolved with the understanding of the immune system and tumors, and any new finding can be translated into the development of more effective cancer vaccines.”
The question remains: are cancer vaccines a viable option for the future of cancer prevention and treatment?
“Prophylactic cancer vaccines are always effective to prevent tumor growth in preclinical animal models; and, therefore, cancer vaccines are highly promising for cancer prevention,” stated Tsuji. “However, development of prophylactic cancer vaccines is still in a very immature development, except for FDA-approved HPV vaccines targeting viral antigens.”
“Preventative cancer vaccines have proved very effective, but we face more challenges when it comes to treatment vaccines,” noted Markman. “Established cancers involve a host of complications and there is still much to be discovered through research.”
“One of important aspects of cancer immunotherapy is that immunotherapy can be combined with other treatments such as surgery, chemotherapy, radiotherapy, and other immunotherapy without negatively affecting therapeutic effects,” added Tsuji.
“Recent findings demonstrated that combination of immunotherapy with chemotherapy or radiotherapy synergistically enhances the therapeutic effects,” he concluded. “I am convinced that cancer vaccines will be one of the standard treatments for a large subset of cancer patients whose immune system can respond to vaccines.”
Catlin Nalley is an associate editor.