Combined Program of Vaccination and Testing for the Human Papilloma Virus Could Eradicate Cervical Cancer

Cervical neoplasia is usually an asymptomatic squamous cell carcinoma caused by human papilloma virus infection (HPV); less often, it is an adenocarcinoma. The recognition that human papilloma virus (HPV) is a cause of cervical cancer has opened new opportunities for the prevention of the disease. Primary prevention is now possible via immunization with highly efficacious HPV vaccines and secondary prevention has gained impetus with the advent of sensitive HPV DNA testing to improve traditional Pap cytology screening programs.

As a result, cervical cancer could be eradicated within the next 50 years. However, according to a cervical cancer screening expert, this can only happen if governments implement national screening programs based on detection of the human papilloma virus (HPV), which causes the disease, together with vaccination programs against the virus.

Professor Jack Cuzick told Europe’s largest cancer congress, ECCO 15 – ESMO 34, (the joint multidisciplinary 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology), meeting in Berlin, Germany (September 20 – 24, 2009) that while the current HPV vaccines protect against two cancer-causing strains of the HPV virus, soon there would be vaccines available that protect against nine types. If vaccination were to be combined with HPV screening (which is much more sensitive than the currently used Pap smear test), then eventually the cancer would disappear in those countries that had successfully implemented national programs. However, this would require political will and effort at both national and European level.

“It’s important to say up front that the HPV is responsible for all cervix cancer,” Cuzick said. “If you can eradicate the virus, the cancer will not appear. So the current vaccine holds the promise of eradicating about 70-75% of cervical cancers (caused by HPV types 16 and 18), and there appears to be some additional cross protection amongst types that are closely related to 16 or 18, in particular 31, 45 and a little bit of 33. There are new vaccines being planned that will vaccinate against nine types. If they are successful, there should be no need to screen women that have been vaccinated at all. That’s the long-term future: vaccination and no screening. After about 50 years, we could see cervical cancer disappearing.”

As the current HPV vaccine only protects against two of the cancer-causing types, vaccinated women will still require screening for the rest of their lives.

“Women vaccinated above the age of about 16 will need to be regularly screened for the rest of their life, because the vaccine is not effective in women who have already been exposed to the virus. Even for girls vaccinated before this age with the current vaccine, there will be a need for some screening to protect from cancers caused by HPV types not in the vaccine, so screening is here to stay for the foreseeable future. However, we need to change to screening for HPV rather than the Pap smear test, and then it will be possible for the tests to be conducted at longer intervals,” said Prof Cuzick, who is the John Snow Professor of Epidemiology and head of department at the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine (London, UK).

The Pap test uses cytology to detect pre-cancerous changes to cells; it relies on subjective assessments by people examining the cells in the smear with a microscope and so is open to human error. Prof Cuzick believes such errors will increase as the proportions of smears with affected cells decline due to increasing numbers of women having been vaccinated. In contrast, the HPV test is almost completely automated, is designed to detect the virus in the smear rather than relying on visual examination, and so is much less likely to be affected by human error.

Prof Cuzick said that countries should be switching to the HPV screening test now. “There’s overwhelming evidence that HPV screening is more effective than the Pap smear test, which misses about a third to a half of all high grade lesions. There are now several available commercial HPV tests and most of these tests show a sensitivity (the proportion of true positives correctly identified) in the order of 95% for high grade lesions, whereas cytology is somewhere between 50-70%. So it would really streamline the service because you could test less frequently, and it’s also been shown that the protection lasts longer so that screening every five to seven years is probably appropriate.”

However, he warned that the European Union and national governments should take the initiative in discussions on implementing screening and vaccination programs, rather than leaving it to pharmaceutical companies to lead the debate.

“The European Commission and Parliament, together with national governments, could be doing more to promote HPV testing. One of the most useful things the EU could do would be to provide a forum for the dissemination of knowledge about the role of HPV both to doctors and to the general public. It could sponsor a major symposium to discuss HPV testing, vaccination and the best strategies for implementing programs in member countries."

“There’s been a lot of concern, particularly with the vaccine, that dissemination of information about HPV has come mainly from the drug companies, and people are, not surprisingly, a little sceptical of pharmaceutical-based education programs. So if the EU was to take this up without pharmaceutical support, I think it would be very appropriate and it would provide a forum that would be extremely legitimate.”

Although current HPV tests are more expensive than cytology tests, Prof Cuzick said the price would go down as the volume of tests increased. In addition, the fact that it’s more accurate and women could be screened at longer intervals meant that switching to HPV testing could save governments money in the long term.

“For younger women we think HPV testing should happen every five years starting at age 25-30; by the time they’re 50, if they’ve been negative, they could probably be screened every eight years. So there’s a lot to be gained, both in terms of better protection and less frequent screening, which will save time and money. If women can go less often and get more protection it makes a lot of sense.”

For more information:

• Oncopolicy session: Drug and lifestyle mediated prevention initiatives in Europe. Thursday 11.15-12.15 hrs CEST (Hall 3)
• Merck Manuals for Healthcare Professionals

Also read these Pubmed Abstracts

• Franceschi S, Cuzick J, Herrero R, Dillner J, Wheeler CM. EUROGIN 2008 roadmap on cervical cancer prevention. Int J Cancer. 2009 Jun 11;125(10):2246-2255. [Epub ahead of print]
• Breitenecker G. [Cervical cancer screening : Past - present - future.] Pathologe. 2009 Sep 16. [Epub ahead of print] German.
• Dinas K, Nasioutziki M, Arvanitidou O, Mavromatidis G, et al. Awareness of human papillomavirus infection, testing and vaccination in midwives and midwifery students in Greece. J Obstet Gynaecol. 2009 Aug;29(6):542-6.
• Lynge E, Antilla A, Arbyn M, Segnan N, Ronco G. What's next? Perspectives and future needs of cervical screening in Europe in the era of molecular testing and vaccination.
  Eur J Cancer. 2009 Oct;45(15):2714-21. Epub 2009 Aug 18.
  Franco EL, Coutlée F, Ferenczy A. Integrating human papillomavirus vaccination in cervical cancer control programmes. Public Health Genomics. 2009;12(5-6):352-61. Epub 2009 Aug 11.
• Ginsberg GM, Edejer TT, Lauer JA, Sepulveda C. Screening, prevention and treatment of cervical cancer-A global and regional generalized cost-effectiveness analysis.
  Vaccine. 2009 Jul 31. [Epub ahead of print]
• Barzon L, Giorgi C, Buonaguro FM, et al, Guidelines of the Italian Society for Virology on HPV testing and vaccination for cervical cancer prevention. Infect Agent Cancer. 2008 Dec 16;3(1):14

Information for your patients:

• Genital HPV Infection - CDC Fact Sheet
• Virus del papiloma humano genital (VPH)
• Center for Young Women's Health
• Merck Manuals (Home Edition) for Patients and Caregivers: Cervical Cancer
• Onco'Zine - The International Cancer Network

Images courtesy American Society of Clinical oncology (ASCO).

Study shows a Survival Benefit with Cancer Vaccine in Glioma.

Data from a Phase I investigator-sponsored trial of the investigational cancer vaccine vitespen (Oncophage®, Antigenics Inc, 3 Forbes Rd, Lexington, MA 02421), an investigational patient-specific vaccine designed to treat cancer with the intent of minimizing adverse events of toxicities in recurrent, high-grade glioma, showed a considerable survival advantage for patients with this disease.

Vaccination with the new cancer vaccine following brain cancer surgery increased overall median survival to approximately 10.5 months with four patients surviving beyond 12 months and one patient surviving almost 2.5 years. This is compared to a historical median survival of only 6.5 months post surgery. All patients enrolled into the trial had at least one recurrence of brain cancer.

The trial was conducted at the Brain Tumor Research Center at the University of California, San Francisco, CA, a center which is internationally recognized as a major research and treatment center for adults and children with tumors of the brain and spinal cord. The data was presented in November 2008 during the Society for Neuro-Oncology’s 13th Annual Scientific Meeting in Las Vegas.

‘These are the most challenging patients to treat because their survival is typically three to six months,’ explained Andrew T. Parsa, MD, PhD, associate professor in the department of neurological surgery at the University of California, San Francisco. ‘These preliminary results suggest a possible impact on survival as well as a very favorable safety profile.’

In addition to survival data, the study also observed a correlation between immune response and overall survival as a result of vaccination with vitespen (n=12; P < .001). These responses were validated by using three separate immune techniques and showed that vitespen evoked a tumor-specific immune response by producing activated T-cells and natural killer cells that can destroy tumor cells. ‘Gliomas develop built-in immunoresistant pathways which play an important role in tumor progression,’ Parsa explained. ‘This study demonstrated significant tumor-specific immune responses leading to a proliferation of T-cells which did not exist in these patients before vaccination with Oncophage. We look forward to completing the Phase II portion of this study and presenting results next year.’

Study Design and Findings
This investigator-sponsored Phase I/II study was designed to evaluate the feasibility, safety and activity of vaccination with vitespen in patients with recurrent, high-grade glioma. Patients were monitored for immune response before and after vitespen treatment using three different techniques.

According to investigators, no adverse events or toxicities identified were considered attributable to the vaccine. A tumor-specific immune response was detected after vaccination in all 12 patients.

Current Regulatory Status
Vitespen is approved in Russia for the adjuvant treatment of kidney cancer patients at intermediate risk for disease recurrence. Outside Russia, vitespen is being evaluated in clinical trials. The drug has been granted fast track and orphan drug status from multiple regulatory bodies, including the US Food and Drug Administration and the European Medicines Agency (EMEA), for the treatment of renal cell carcinoma and metastatic melanoma.

Glioma
Gliomas are the most common type of brain tumor and is currently a fatal disease impairing areas such as thinking, personality and movement. The National Cancer Institute estimates that about 19,000 cases are diagnosed every year in the U.S and according to historical estimates, the median survival of patients with previously treated glioma is typically three to six months.
The outlook for patients with gliomas is generally poor. The median survival for patients with moderately severe or grade III gliomas is 3 - 5 years. The median survival for patients with grade IV glioma, the most severe and aggressive form of the disease also called glioblastoma multiforme, is less than a year.

Personalized medicine
Vitespen offers a unique, personalized, opportunity for the treatment of individual patients.
Derived from each individual’s tumor, the vaccine consists of purified complexes of tumor-derived HSPs linked to tumor antigen peptides which consists the ‘antigenic fingerprint’ of the patient’s particular cancer. This ‘antigenic fingerprint’ is designed to reprogram the body’s immune system to target only cancer cells bearing this specific fingerprint.

When these purified complexes are re-administered to a patient antigenic tumor peptides are expressed on the surface of potent antigen-presenting cells of the immune system, such as macrophages and dendritic cells. This stimulates a more powerful anti-tumor immune response than that generated by expression of the same antigens by the tumor cell. The result is that activated T-cells directly target and destroy cancer cells bearing the specific ‘fingerprint’.

Vitespen is designed to target only cancerous cells and to leave healthy tissue unaffected. As a result, vaccination with this cancer drug limits the toxicities and debilitating side effects typically associated with traditional cancer treatments such as broad-acting cancer chemotherapy and radiation therapy.

Mode of Action
Heat-shock proteins (HSPs) also called stress proteins, are the most abundant and ubiquitous soluble intracellular proteins. They are present in all cells in all life forms and induced when a cell undergoes various types of environmental stresses like heat, cold and oxygen deprivation.
Despite the obvious importance of stress responses, heat shock proteins have only recently been examined for the role they play in the control of disease pathology and in the survival and virulence of pathogens. For example, research has shown that a number of heath shock proteins protect against oxidative damage, conveys peptide antigens for presentation to the immune system, and can protect against cardiac failure.

Various forms of heat shock proteins are involved in binding and stabilizing proteins at intermediate stages of folding (essential for protein function), assembly and translocation and degradation. They interact with antigen-presenting cells (APCs) through CD91 and other receptors, eliciting a cascade of events that includes representation of HSP-chaperoned peptides MHC, translocation of NF-kappaB into the nuclei, and maturation of dendritic cells. The key role heath shock proteins play in fundamental immunologic phenomena allow them to be used for immunotherapy of cancers and infections in new and exciting ways.

For more information, read Pubmed abstracts:

• Testori A, Richards J, Whiteman E, et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. J Clin Oncol. 2008 Feb 20;26(6):955-62
  http://www.ncbi.nlm.nih.gov/pubmed/18281670
• Amato RJ. Heat-shock protein-peptide complex-96 for the treatment of cancer. Expert Opin Biol Ther. 2007 Aug;7(8):1267-73.

Also see

• Christopher Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial The Lancet, Volume 372, Issue 9633, Pages 145 - 154, 12 July 2008.
• Yang JC. Vitespen: a vaccine for renal cancer? The Lancet, Volume 372, Issue 9633, Pages 92 - 93, 12 July 2008
• Heat Shock Proteins: How They Work (animation);
• Heat Sock Proteins – How they work (downloadable graphic overview);
• Heat shock proteins ‘mechanism of action’ diagram.

Information for physicians:

• Clinical trials: Brain and Central Nervous System Tumors
  ClinicalTrials.gov Identifier: NCT00293423

Information for your patients:

• National Cancer Institute: Brain Tumor Home Page.
• NOB/Neuro-Oncology Branch. A trans-institute program of the National Cancer Institute and National Institute of Neurologic Diseases and Stroke of the National Institutes of Health. About brain cancer.
• Mayo Clinic medical services: Glioma
• MedlinePlus® Patient Education: Brain Cancer.