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 fourth most frequently diagnosed cancer among women worldwide. In the U.S. in 2016, there will be 12,990 new cases of invasive cervical cancer and 4,120 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 26 may also receive Gardasil-9® 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 benefit. Immunotherapy approaches designed to treat these types of cancer are badly needed.ancers, 70% of vulvar cancers, and 60% of penile cancers.
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.
Pembrolizumab (Keytruda®), a PD-1 antibody, is being tested in a phase II trial for patients with cervical, vulvar, or anal cancer (NCT02628067).
Nivolumab (Opdivo®), a PD-1 antibody, is being tested in a phase I/II for patients with viral-associated cancers, including cervical cancer, vaginal cancer, and vulvar cancer (NCT02488759).
Ipilimumab (Yervoy®), an anti-CTLA-4 antibody, is being tested in a phase I study of chemoradiation followed by ipilimumab for patients with locally advanced cervical cancer (NCT01711515). One of the investigators on this trial—W. Martin Kast, Ph.D.—was awarded a CRI Clinic and Laboratory Integration Program (CLIP) grant to test if chemotherapy boosted ipilimumab in cervical cancer.
Durvalumab (MEDI4736), an anti-PD-L1 antibody, is being tested in combination with tremelimumab, an anti-CTLA-4 antibody, in a phase I trial for patients with six kinds of cancer, including cervical cancer (NCT01975831). This trial is sponsored jointly by the CRI/Ludwig Clinical Trials Network.
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 II clinical trial of TVGV-1 vaccine for patients with HPV-induced cervical pre-cancer (NCT02576561).
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), 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 in patients with anal cancer (NCT01671488).
There are two phase I clinical trials testing pNGVL4a/E7 (Detox)/HSP70 DNA vaccine in patients with HPV16+ cervical intraepithelial neoplasia. 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 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 for patients with HPV-related cancers, including cervical cancer (NCT01585428).
A phase II study of T cells genetically engineered to target HPV16 E6 in patients with cervical cancer, vaginal cancer, anal cancer, and penile cancer (NCT02280811).
A phase I study of T cells genetically engineered to be resistant to TGFβ, which the HPV-cancers produce, in patients with cervical cancer, vulvar cancer, anal cancer, and penile cancer (NCT02379520).
Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors. Bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF) that helps tumors form new blood vessels to get nutrients (a process known as angiogenesis), is FDA approved for the treatment of recurrent or late-stage cervical cancer.
HuMax®-TF-ADC, an antibody drug conjugate targeting tissue factor-specific cells, is being tested in two clinical trials in patients with advanced cancer, including cervical cancer (NCT02001623, NCT02552121).
IMMU-132, an antibody drug conjugate targeting the TROP-2 antigen, which is expressed in a variety of cancers, is being tested in a phase I/II trial in patients with advanced cancer, including cervical cancer (NCT01631552).
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% .
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 2016, CDC HPV-Associated Cancers, National Cancer Institute, Globocan 2012, Cancer.net, CRI grantee documents
Last Updated February 2016
 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)
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