Cancer Immunotherapy

Cervical Cancer

Cervical cancer is one of the major cancer types for which new immune-based cancer treatments are currently in development. This page features information on cervical cancer and immunotherapy clinical trials for cervical cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to people with cervical cancer.

By far, the most significant cause of cervical cancer, as well as other ano-genital cancers, is infection with a virus—the human papillomavirus (HPV). HPV is thought to cause nearly all cases of cervical cancer, 90% of anal cancers, 75% of vaginal cancers, 70% of vulvar cancers, and 60% of penile cancers. HPV is also a significant cause of head and neck cancers.

Cervical cancer is the third most frequently diagnosed cancer among women worldwide. In the U.S. in 2014, there were 12,360 new cases of invasive cervical cancer and 4,020 deaths. Globally, there are approximately 530,000 cases of cervical cancer per year, and 265,000 deaths. If cervical cancer is caught while it is still localized, the 5-year survival rate is 91%. The 5-year survival rates for patients with regional and distant disease are 57% and 16%, respectively.

Cervical cancer is usually a slow-growing cancer that may not cause symptoms, but it can be found early with regular Pap tests (a procedure in which cells are scraped from the cervix and looked at under a microscope). Mortality rates have been decreasing in the U.S., thanks largely to widespread use of the Pap test as a screening tool. In addition to the Pap test, a DNA tests can also detect HPV strains that pose a cervical cancer risk. Symptoms tend not to occur until the cancer has become invasive. Abnormal vaginal bleeding is the most common sign of cervical cancer.

Three FDA-approved vaccines, Gardasil®, Gardasil-9®, and Cervarix®, prevent HPV infection and therefore guard against the major cause of cervical and ano-genital cancers and potentially head and neck cancer. Gardasil-9® is approved for the prevention of cervical, vulvar, vaginal, and anal cancers caused 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, whereas the older version Gardasil® protects against the HPV types 16, 18, 6, and 11. Young men between the ages of 9 and 15 may also receive an HPV vaccine to protect their future partners and to protect themselves against anal cancer and potentially head and neck cancer, as well as genital warts. Cervarix is FDA approved for use in preventing the two strains of HPV that cause most cervical cancers, HPV 16 and 18.

For people already infected with HPV or facing a cervical or ano-genital cancer diagnosis the FDA-approved vaccines are of no use . Immunotherapy approaches designed to treat these types of cancer are badly needed.

Immunotherapy for Cervical Cancer

Several approaches to T cell based-immunotherapy for cervical cancer have shown promise in early clinical trials.

Checkpoint Inhibitors/Immune Modulators

A promising avenue of clinical research in cervical cancer is the use of T cell immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances in the regulation of T cell immune responses. By blocking inhibitory molecules or, alternatively, activating stimulatory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer T cell immune responses. Several checkpoint inhibitors, targeting multiple different checkpoints, are currently in development.

  • Ipilimumab (Yervoy®), an anti-CTLA-4 antibody made by Bristol-Myers Squibb, is being tested in two clinical trials for patients with cervical cancer: a phase II study of ipilimumab for HPV+ cervical cancer that is metastatic or recurrent  (NCT01693783), and a phase I study of chemoradiation followed by ipilimumab for patients with locally advanced cervical cancer (NCT01711515).
  • MEDI6469, an OX40 immune modulator made by MedImmune/AstraZeneca, is being tested in combination with tremelimumab, an anti-CTLA-4 antibody, or MEDI4736, an anti-PD-L1 antibody, in a phase I/II trial for patients with advanced solid tumors (NCT02205333).
  • MEDI4736, a PD-L1-targeting antibody made by MedImmune/AstraZeneca, is being tested in a phase I/II trial for patients with advanced solid tumors (NCT01693562).
  • MEDI4736, an anti-PD-L1 antibody, is being tested in combination with tremelimumab, an anti-CTLA-4 antibody, in two phase I trials for patients with solid tumors (NCT02261220) and patients with six kinds of cancer, including cervical cancer (NCT01975831). The latter trial is sponsored jointly by the CRI/Ludwig Clinical Trials Network.
  • Urelumab (BMS-663513), an anti-4-1BB/CD137 antibody, and nivolumab, an anti-PD-1 antibody, both made by Bristol-Myers Squibb, are being tested in a phase I/II trial in adult patients with solid tumors (NCT02253992).
  • Urelumab (BMS-663513), an anti-4-1BB/CD137 antibody made by Bristol-Myers Squibb, is being tested in a phase I trial in patients with advanced cancers (NCT01471210).
  • Lirilumab (BMS-986015), an anti-KIR antibody, is being tested in combination with nivolumab, an anti-PD-1 antibody, in a phase I study for patients with advanced solid tumors (NCT01714739).
  • MPDL3280A, an anti-PD-L1 antibody being developed by Genentech, is being tested in a phase I trial for numerous cancers (NCT01375842).
  • MK-4166, an anti-GITR antibody made by Merck, is being tested in a phase I trial for patients with advanced solid tumors (NCT02132754).
  • MOXR0916, an anti-OX40 agonist antibody being developed by Genentech, is being tested in a phase I trial for patients with locally advanced and metastatic solid tumors (NCT02219724).
  • MEDI6383, an OX40 agonist being developed by MedImmune/AstraZeneca, is being tested in a phase I trial for patients with solid tumors (NCT02221960).
  • MEDI0680 (AMP-514), an anti-PD-1 antibody developed by MedImmune/AstraZeneca, is being tested in a phase I trial for patients with advanced cancers (NCT02013804).
  • MEDI0680 (AMP-514) in combination with MEDI4736, an anti-PD-L1 antibody, is being tested in a phase I trial for patients with advanced cancers (NCT02118337).

Therapeutic Vaccines

Cancer vaccines are designed to elicit a T cell immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens.

  • A phase I/II trial of VGX-3100, a vaccine that targets HPV types 16 and 18, and INO-9012, a DNA construct that induces human interleukin 12 (IL-12), both made by Inovio Pharmaceuticals, are being tested in patients with cervical cancer (NCT02172911).
  • ADXS11-001, a vaccine against the E7 protein, which is made by HPV, is in phase I/II trials by the bioscience company Advaxis. It is being tested in combination with the MedImmune/AstraZeneca drug MEDI4736, a PD-L1 inhibitor, in patients with cervical cancer (NCT02291055) and as a single agent in patients with HPV+ cervical cancer (NCT02164461). It is also in phase I/II testing for anal cancer (NCT01671488).
  • There are two phase I clinical trials testing pNGVL4a/E7 (Detox)/HSP70 DNA vaccine in patients with HPV16+ cervical intraepithelial neoplasia, taking place at the Sidney Kimmel Comprehensive Cancer Center. The first one will determine the best dose (NCT00988559) and the second one will be a combination with imiquimod, an innate immune activator (NCT00788164).

Adoptive T Cell Therapy

Another avenue of immunotherapy for cervical cancer is adoptive T cell transfer. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the T cell immune system’s anti-cancer response. The following study is currently enrolling patients:

  • A phase II study of white blood cells taken from the patient’s own tumor is being conducted at the National Institutes of Health Clinical Center for patients with HPV-related cancers, including cervical cancer (NCT01585428).

Monoclonal Antibodies

Monoclonal antibodies (mAbs) are molecules, generated in the lab, that target specific antigens on tumors. Bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF), is FDA-approved for the treatment of recurrent or late-stage cervical cancer.

  • A phase Ia trial of OMP-52M51, an anti-cancer stem cell antibody that binds to the Notch1 receptor, is enrolling patients with solid tumors (NCT01778439).


CRI Contributions and Impact

Since 1983, Cancer Research Institute (CRI) has awarded more than $12 million dollars for cervical cancer and human papillomavirus research.

  • In 1999, CRI awarded the first of several grants to Ian H. Frazer, M.D., FRCPA, for work on “virus-like particles” (VLP) based papillomavirus vaccines. This work was crucial to the development of Gardasil, the first preventative vaccine against cervical cancer. Gardasil was approved by the FDA in 2006. A newer version, Gardasil-9®, was FDA approved in 2014. It protects against nine types of HPV that cause approximately 90% of all cases of cervical cancer worldwide.

“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, Ph.D., and Cornelis (Kees) Melief, M.D., Ph.D., at Leiden University Medical Center, found in a CRI sponsored study that a vaccine composed of HPV long peptides could demonstrate 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% [1].
  • In 2014, W. Martin Kast, Ph.D., was awarded a Clinic and Laboratory Integration Program (CLIP) grant from CRI to test a treatment that combines chemoradiation and ipilimumab (Yervoy®), a checkpoint inhibitor that “takes the brakes off” immune cells. Dr. Kast hopes that combining chemotherapy with immunotherapy might be an effective way to trigger a targeted immune attack against cervical cancer cells and lead to a much-needed treatment for cervical cancer patients (NCT01711515).

Sources: Cancer Facts and Figures 2014, CDC HPV-Associated Cancers, National Cancer Institute, Globocan 2012,, CRI grantee documents

Last Updated February 2015

[1] Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 2009 Nov 5; 361: 1838-1847. (PMID: 19890126)


Cervical Cancer News & Stories

Reviewed By:

W. Martin Kast is a cervical cancer expert
W. Martin Kast, Ph.D.
USC/Norris Comprehensive Cancer Center Los Angeles, CA

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