For Cervical Cancer

How is Immunotherapy for Cervical Cancer Changing the Outlook for Patients?

Reviewed by:

Dmitriy Zamarin, MD, PhD
Memorial Sloan Kettering Cancer Center

Immunotherapy for cervical cancer shows promise with preventive vaccines and new treatment directions.

Cervical cancer is the fourth most common cancer in the world for women, affecting over half a million people every year. Almost all cases of cervical cancer are associated with human papilloma virus (HPV) infection. This prevalent virus is also linked to anal, genital, and head and neck cancers. Most people infected by HPV do not develop cancers associated with the virus.

During the early stages, cervical cancer can usually be detected early with regular Pap smear, also called a Pap test, a procedure in which cells are scraped from the cervix and looked at under a microscope. Mortality rates have been decreasing in United States, thanks largely to widespread use of the Pap smear as a screening tool. In addition to the Pap smear, DNA tests can also detect HPV strains that pose a cervical cancer risk. Cervical cancer incidence and mortality, however, remain significantly higher in low-income countries.

Symptoms of this disease often go undetected until the cancer becomes invasive. Abnormal vaginal bleeding is the most common sign of cervical cancer.

There are an estimated 570,000 new cases of cervical cancer diagnosed and 310,000 cervical cancer-related deaths each year globally, and in 2023 there will be an estimated 14,000 new cases and 4,000 deaths in the United States alone. If cervical cancer is caught while it is still localized, the five-year survival rate is 92%. The five-year survival rates for patients with regional and distant disease are 57% and 17%, respectively.

Three immunotherapy vaccines (below) are FDA-approved to prevent HPV infection. Since the introduction of the first HPV vaccine in 2006, the number of new cases of cervical cancer has dropped significantly in the United States. Recent studies have begun to provide evidence that vaccination may also provide some benefit to people who have been infected previously with HPV. While these vaccines are effective in preventing HPV infection, there is no evidence that the vaccines are effective against established cancers.

Preventive 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 cervical, vulvar, vaginal, and anal cancers
  • Gardasil®: a vaccine that protects against infection by HPV types 16, 18, 6, and 11; can help prevent the development of HPV-related cervical, vulvar, vaginal, and anal 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 cervical, vulvar, vaginal, and anal cancers

Cervical Cancer Treatment Options

Standard treatment options for cervical cancer are surgery, radiation therapy, chemotherapy, and targeted therapy.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are currently three FDA-approved immunotherapy options for the treatment of cervical cancer.

Targeted Antibodies

  • Bevacizumab (Avastin®): a monoclonal antibody that targets the VEGF/VEGFR pathway and inhibits tumor blood vessel growth; approved for subsets of patients with advanced cervical cancer in combination with chemotherapy
  • Tisotumab vedotin (Tivdak™): an antibody-drug conjugate that targets tissue factor (TF); approved for subsets of patients with advanced cervical cancer


  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced cervical cancer that has PD-L1 expression, high microsatellite instability (MSI-H), DNA mismatch repair deficiency (dMMR), or high tumor mutational burden (TMB-H)

Other vaccines and immunotherapies that target HPV-infected tumors are also currently being tested in clinical trials.

CRI’s Impact in Cervical Cancer

Since 1953, the Cancer Research Institute has dedicated more than $10 million in funding to develop and discover immunotherapies that can treat gynecologic cancers, including cervical cancer. CRI’s support of cervical cancer and human papillomavirus research has led to several breakthroughs in treatment, including paving the way for more effective prevention methods.

  • In 1999, CRI awarded the first of several grants to Ian H. Frazer, MD, FRCPA, for work on “virus-like particles” (VLP) based papillomavirus vaccines—crucial to the development of the first preventive cervical cancer vaccine, Gardasil®.

“This new vaccine that prevents cervical cancer grew out of research funded by CRI.”

Professor Ian Frazer, 2003 CRI Annual Report
  • In 2009, Sjoerd van der Burg, PhD, and Cornelis (Kees) Melief, MD, PhD, at Leiden University Medical Center, found in a CRI-sponsored study that a vaccine composed of HPV long peptides could result in durable complete responses in some women with HPV 16+ vulvar intraepithelial neoplasias (VINs), a disease that normally has a spontaneous regression rate of less than 2%.
  • In 2014, W. Martin Kast, PhD, was awarded a Clinic and Laboratory Integration Program (CLIP) grant from CRI to test a treatment that combines chemoradiation and the immunotherapy ipilimumab (Yervoy®) to trigger a targeted immune attack against cervical cancer cells and lead to a much-needed treatment for cervical cancer patients.
  • In 2020, Sjoerd van der Burg, PhD, and Cornelis (Kees) Melief, MD, PhD, at Leiden University Medical Center, revealed the benefits of a vaccine-chemotherapy combination in advanced, HPV-associated cervical cancer.

You can explore CRI’s current funding for cervical cancer research in our funding directory.

Related Links

Cervical Cancer Statistics

4th Most frequently diagnosed cancer of women worldwide

91% 5-year survival rate for localized disease

$12 Million Awarded by CRI to cervical cancer research

570K Newly diagnosed patients each year globally

Cervical Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in cervical cancer clinical trials include:

  • 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 cancer and associated with metastasis
  • Tissue Factor (TF): a protein expressed by cancer cells that aids proliferation and metastasis
  • TROP2: a protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in cervical cancer clinical trials include:

  • Folate-related proteins: proteins in this pathway are commonly overexpressed in cancer
  • Human Papilloma Virus (HPV)-related antigens: foreign viral proteins expressed by HPV-infected cancer cells
  • Personalized neoantigens: these abnormal markers arise from mutations and are expressed exclusively by tumor cells
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in cervical cancer clinical trials include:

  • GD2: a pathway that controls cell growth, adhesion, and migration, and is often abnormally overexpressed in cancer cells
  • 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 can become reactivated in cancer cells, flagging them as abnormal to the immune system
  • 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

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in cervical cancer clinical trials include:

  • CD73 or A2AR: blocking these pathways can help prevent the production of immunosuppressive adenosine
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages
  • CTLA-4: blocking this pathway can help promote expansion and diversification of cancer-fighting T cells
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • ICOS: activating this co-stimulatory pathway on T cells can help enhance immune responses against cancer
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate immune responses against tumors

Oncolytic virus therapy uses viruses that are often, but not always, modified in order to infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in cervical cancer clinical trials include:

  • Adenovirus: a family of common viruses that can cause a wide range of typically mild effects including sore throat, fatigue, and cold-like symptoms
  • Measles virus: a highly contagious virus that infects the respiratory tract and can cause measles
  • New Castle Virus: a virus primarily found in birds; can cause mild conjunctivitis and flu-like symptoms in humans
  • Vaccinia virus: the virus that was used to help vaccinate against and eliminate smallpox; rarely causes illness in humans and is associated with a rash covering the body
  • Vesicular stomatitis virus: a virus that belongs to the same family as the rabies virus; can cause flu-like symptoms in humans

Find an Immunotherapy Clinical Trial

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