During the Development of Therapeutic Cancer Vaccines conference held in Los Angeles, April 27-29, 2003, recent advances in the development of vaccines to prevent and treat human papilloma virus (HPV) associated cervical cancer. This conference was sponsored by the John Wayne Cancer Institute, the Association of Biologics and the Royal Society of Medicine.

Ian Frazer from Brisbane, Australia reviewed the progress of efforts to develop vaccines against HPV for prevention of infection, prevention of cervical cancer and for therapy of established cervical cancer. ¹

There are 250,000 deaths world wide from HPV caused cervical cancer. The number of deaths is high because most of the developing word do not have routine screening for cervical cancer, therefore most patients present late in the disease course. HPV is the sole cause of cervical cancer. HPV type 16 is the most common. After the onset of infection, cervical cancer can occur from 2 to as long as 50 years after the onset of infection. Over 5 million women, most in developing countries, are already infected with HPV. This statistic demonstrates the importance of developing a therapeutic vaccine.

Prevention of HPV infection should prevent cervical cancer. There are currently 55 different vaccine products directed at HPV in preclinical testing. These products include “synthetic peptides, recombinant non-structural viral proteins, polynucleotide vaccines encoding all or part of the non-structural proteins on the virus and live viral vectors including papilloma virus antigens.” The vaccines that are currently in phase III clinical trials and are based on virus-like particles produced using recombinant DNA technology and incorporating the L1 capsid protein of the relevant papilloma type.

In clinical trial, an HPV vaccine was demonstrated 100% effective in preventing type 16 and 18 infection. This was a randomized trial conducted in sexually active women who were negative at the time of enrollment. Among 765 patients, there were 41 cases of HPV in the control group and nine in the treated group, six of which were transient.

Development of vaccines is limited by the following factors:

• HPV does not grow in culture.
• Current vaccines have no cell-mediated immunity, only antibody immunity.
• Radiation and chemotherapy interfere with the development of immunity. HPV specific Vaccines are unlikely to work in the therapeutic setting because of “mutations in the MHC system impairing antigen presentation.”
• Studying cancer prevention in developed countries is difficult since Pap smears and HPV culturing detects both infection and dysplasia, which can be cured by surgical removal.
  

CerVax™ Unique approaches to treatment will be necessary for HPV vaccination to be effective. For example, it will be necessary to combine vaccines representing different types and to determine how long immunity would last. Another approach consists of adding adjuvants to increase the immune response. CerVax™, a vaccine that is in phase I trials in Australia, combines a powerful adjuvant from tree bark. In this trial, women with high grade cervical lesions treated with CerVax™ showed a decrease in virus load prior to surgery. “Viral loads were wide at start and fell in all who had vaccine”.

Dr Frazer concluded by acknowledging that the problems with a therapeutic vaccine would probably be great due to mutations that occur over time as cervical cancer develops.

CoVal™ Dr. John Neefe, from Stress Biotechnologies Inc, reported progress on CoVal™ for prevention of HPV infection. ² The strategy of CoVal™ development consists of a heat shock protein (HSP65) and E7, which is an antigen associated with HPV type 16. E7 is the most prevalent antigen in cervical cancer. This fusion molecule is a non-self antigen which induces specific antibody response with little if any T cell reactivity. The vaccine is made in E coli and is frozen, thus it is easy to meet most of the FDA requirements for quality control. It was reported that over 500 healthy volunteers and patients had received this vaccine.

Previous studies have shown that vaccination of sexually active women who were negative for HPV could prevent acquisition of HPV infection. CoVal™ has also been demonstrated effective in anal dysplasia, genital warts, and respiratory infections.

Anal dysplasia is a precursor lesion to anal cancer and is more difficult to treat than dysplasia of the cervix. However, since all women with dyplasia are treated with surgery, anal dysplasia is an easier disease to evaluate vaccine efficacy. A phase II randomized trial using a dose of vaccine of 100 micrograms of CoVal™ did not show benefit. However, when these same patients were treated with a dose of 500 micrograms, 50% showed a decrease in dysplasia by 100 days. However, it took one year for 80 of patients to improve and 18 months for 95% to improve. These results have occurred despite the fact that only 20% of patients have infection with type 16 HPV suggesting cross reactivity of the vaccine. The current study randomizes patients to 500 micrograms given three times versus a placebo.

Genital warts are associated with HPV types 6 and 11 which are not targeted by this CoVal™. However, in 23 patients there was a 75% reduction in genital warts but the response took up to 15 months. In a randomized trial CoVal™ resulted in a 52% reduction in genital warts at 6 months compared to 13% in the placebo arm.

HPV can also cause pulmonary infections which can lead to respiratory obstruction in children. A phase II trial of CoVal™ in 27 children with HPV pulmonary infection has been performed and the effects are presumed to be positive.

References

1. Frazer I, E6, E7 and VLP Based Papillomavirus Vaccines for Prevention of Cervical Cancer. Development of Therapeutic Cancer Vaccines conference held in Los Angeles, April 27-29, 2003

2. Neefe J, CoVal™ Fusions: A Therapeutic Vaccine Platform Utilizing Head Shock Proteins (HSP) to Treat Chronic Viral Infections. Development of Therapeutic Cancer Vaccines conference held in Los Angeles, April 27-29, 2003