Immunotherapy:
Cancer Vaccines

Cancer Vaccines: Preventive, Therapeutic, Personalized

Reviewed by:

Gavin P. Dunn, MD, PhD
Washington University School of Medicine in St. Louis

Cancer vaccines are a form of immunotherapy that can help educate the immune system about what cancer cells “look like” so that it can recognize and eliminate them.

Vaccines have proven effective in preventing diseases caused by viruses and bacteria. Since the first vaccine was developed more than 200 years ago, they have prevented some of the twentieth century’s deadliest diseases and have helped save hundreds of millions of lives globally.

In the case of diseases caused by viruses (e.g., measles, polio, and smallpox) and bacteria (e.g., diphtheria, tetanus, and tuberculosis), vaccines work by exposing people to a weakened or inactivated version of the threat. This enables their immune system to identify these threats according to their specific markers—known as “antigens”—and mount a response against them. These vaccines typically work best in the preventive setting, when an individual is given the vaccine before being infected by the bacteria or virus.

In the case of cancer, however, the situation is more complicated for several reasons (more below), which has made it more difficult to develop vaccines to prevent or treat cancer. In particular, unlike bacteria and viruses, which appear foreign to our immune system, cancer cells more closely resemble our normal, healthy cells. Furthermore, each individual’s tumor is in some sense unique and has its own distinguishing antigens. As a result, more sophisticated approaches are necessary to develop effective cancer vaccines.

Preventive Cancer Vaccines

Viral infections are responsible for the development of several cancers, and preventive vaccines play an important role in reducing risk. For instance, cervical cancer and head and neck cancer can be caused by human papillomavirus, or HPV, whereas liver cancer can be caused by hepatitis B virus or HBV. Several vaccines have been developed that can prevent HBV and HPV infection and, as a result, protect against the formation of HBV- and HPV-related cancers. Four of these preventive cancer vaccines have been approved by the U.S. Food and Drug Administration (FDA).

Therapeutic Cancer Vaccines

Each individual’s tumor is in some sense unique and has its own distinguishing antigens. As a result, more sophisticated cancer vaccine approaches are necessary.

Fortunately, doctors can now identify targets on patients’ tumors that can help distinguish cancer cells from their normal cells. Sometimes these targets are normal proteins that are produced at abnormally high levels by cancer cells, such as prostatic acid phosphatase (PAP), which is often overexpressed by prostate cancer cells. Taking advantage of that insight, the sipuleucel-T vaccine was developed and received FDA approval in 2010 for the treatment of patients with advanced prostate cancer. Additionally, virus-derived proteins expressed by virus-infected cancer cells offer another promising source of markers that can be targeted through vaccines.

Another exception is Bacillus Calmette-Guérin, or BCG, a tuberculosis vaccine that acts as a general immune stimulant. In 1990, BCG became the first immunotherapy of any type to be approved by the FDA and is still used for the treatment of early-stage bladder cancer.

Personalized Neoantigen Vaccines

In contrast to normal-yet-overexpressed proteins like PAP, tumors also display unique targets that arise as a result of mutations. These are referred to as neoantigens (“new antigens”), and they are expressed exclusively by tumor cells and not by any of a patient’s healthy cells. With neoantigen vaccines, therefore, it is conceivable that immune responses could be directed precisely against patients’ tumor cells while sparing their healthy cells from immune attack, thus possibly preventing side effects.

In addition to the previously mentioned vaccines, several types of neoantigen vaccines are currently being evaluated, both alone and in combination with other treatments, in a variety of cancer types in clinical trials.

Cancer Vaccine Treatment Options

There are currently four vaccines that are approved by the FDA that can help prevent cancer, in addition to two FDA-approved vaccines for the treatment of cancer:

Preventive Cancer Vaccines

• Cervarix®: a vaccine approved for use in preventing infection by the two strains of HPV that cause most cervical cancers, HPV types 16 and 18; can help prevent the development of HPV-related anal, cervical, head and neck, penile, vulvar, and vaginal cancers
• Gardasil®: a vaccine that protects against infection by HPV types 16, 18, 6, and 11; can help prevent the development of HPV-related anal, cervical, head and neck, penile, vulvar, and vaginal cancers
• Gardasil-9®: a vaccine approved for the prevention of infection by HPV types 16, 18, 31, 33, 45, 52, and 58, and for the prevention of genital warts caused by HPV types 6 or 11; can help prevent the development of HPV-related anal, cervical, head and neck, penile, throat, vulvar, and vaginal cancers
• Hepatitis B (HBV) vaccine (HEPLISAV-B®): a preventive vaccine that protects against infection by the hepatitis B virus; can help prevent the development of HBV-related liver cancer

Therapeutic Cancer Vaccines

• Bacillus Calmette-Guérin (BCG): a vaccine that uses weakened bacteria to stimulate the immune system; approved for patients with early-stage bladder cancer
• Sipuleucel-T (Provenge®): a vaccine composed of patients’ own stimulated dendritic cells; approved for prostate cancer

Side Effects

Side effects may vary according to the type of cancer vaccine—and what exactly it targets—and may also be influenced by the location and type of cancer as well as a patient’s overall health. Potential cancer vaccine-related side effects may result from a misdirected immune response where the immune system targets healthy cells that express the same target proteins. Patients should consult their medical care team to gain a better and fuller understanding of the potential risks and side effects associated with specific cancer vaccines.

Common side effects associated with currently approved cancer vaccines may include but are not limited to: anorexia, back pain, chills, fatigue/malaise, fever, flu-like symptoms, headache, joint ache, myalgia, nausea, and neuralgia.

CRI’s Impact in Cancer Vaccines

Throughout CRI’s history, we have supported a variety of basic research projects aimed at improving our understanding of the principles behind vaccines and strategies to identify the most promising vaccine targets, as well as translational and clinical efforts that seek to use these insights in the development of cancer vaccines for patients in the clinic.

In 1959, Lloyd J. Old, MD, CRI’s founding scientific and medical director, showed that the tuberculosis vaccine Bacillus Calmette-Guérin (BCG) could inhibit tumor growth in mice. Then, in 1980, CRI-funded grantee Alvaro Morales, MD, of Queen’s University (Canada), demonstrated that BCG can prevent bladder cancer recurrence in human patients. The FDA approved the use of BCG for superficial bladder cancer in 1990.

Additionally, CRI has supported over two decades of research on the NY-ESO-1 antigen, a cancer vaccine target. In 2017, CRI grantees Sacha Gnjatic, PhD, of the Icahn School of Medicine at Mount Sinai, and Kunle Odunsi, MD, PhD, of the Roswell Park Comprehensive Cancer Center, found that vaccines against NY-ESO-1 were associated with improved survival in patients with aggressive ovarian cancer. This was based on work throughout the 2000s from CRI-funded scientists—including Maha Ayyoub, MD, PhD, Nina Bhardwaj, MD, PhD, Dirk Jaeger, MD, Elke Jaeger, MD, Alexander Knuth, MD, Lloyd J. Old, MD, Gerd Ritter, PhD, and Danila Valmori, PhD—that advanced our understanding and development of NY-ESO-1-targeting vaccines in a variety of cancers.

Other important contributions made by CRI scientists in the area of cancer vaccines include:

• In 2001, CRI grantee Ian H. Frazer, MD, of the University of Queensland, made important breakthroughs regarding human papillomavirus (HPV)-targeting vaccines that paved the way for the development of the first preventive cervical cancer vaccine, Gardasil®.
• In 2009, CRI grantees Sjoerd van der Burg, PhD, and Cornelis Melief, MD, PhD, both of the Leiden University Medical Center, found that a vaccine composed of human papillomavirus (HPV) long peptides could produce durable complete responses in some women with HPV-16+ pre-cancer of the vulva.
• In 2012, CRI predoctoral fellow Matthew Vesely, PhD, and CRI grantee Robert Schreiber, PhD, highlighted how next-generation sequencing could be used to characterize tumor neoantigens for the development of vaccines.

Currently, CRI is funding several grantees whose research involves cancer vaccines, including deciphering decipher the rules that govern the intracellular processing of (neo-)antigens and their presentation on the surface of cells, exploring the use of nanoparticles to deliver “intel” to the immune system about what cancer “looks like,” and analyzing patients whose immune systems naturally eliminated hepatitis C virus (HCV) infections. CRI is also providing funding support for a phase 1/2 clinical trial (NCT03164772) combining two checkpoint inhibitors with a cancer vaccine in patients with advanced lung cancer.

Cancer Vaccine Clinical Trial Targets

Vaccine targets under evaluation in clinical trials include:

• 5T4: an antigen often expressed by several different types of cancers
• CEA: a protein involved in cellular adhesion normally produced only before birth; often abnormally expressed in cancer and may contribute to metastasis
• Cytomegalovirus (CMV)-related antigens: foreign viral proteins expressed by CMV-infected cancer cells
• Folate-related proteins: proteins in this pathway are commonly overexpressed in cancer
• EGFR: a pathway that controls cell growth and is often mutated in cancer
• HER2: a pathway that controls cell growth and is commonly overexpressed in breast cancer and is associated with metastasis, or disease spread
• Human Papilloma Virus (HPV)-related antigens: foreign viral proteins expressed by HPV-infected cancer cells
• MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but cancer cells often reactivate their expression
• Mesothelin: a protein that is commonly overexpressed in cancer and may aid metastasis

• MUC-1: a sugar-coated protein that is commonly overexpressed in cancer
• NY-ESO-1: a protein that is normally produced only before birth but is often abnormally expressed in cancer
• P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
• PAP and PSA: enzymes made by prostate cells that is often overproduced by prostate tumors
• Personalized neoantigens: these abnormal markers arise from mutations and are expressed exclusively by tumor cells
• Ras: a central signaling protein that is commonly mutated in cancer and has been linked to abnormal growth and cell division
• Survivin: a protein that can prevent cellular death and is overexpressed by a number of cancer cell types
• Telomerase: an enzyme that helps maintain the health of cellular DNA; exploited by cancer cells to achieve immortality
• Tumor-associated antigens: antigens often expressed at abnormally high levels on tumor cells and can be used to target them; also found on normal cells at lower levels
• WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor

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