Despite the demonstrated efficacy of screening programs, cervical cancer continues to be a significant health issue. In 1999 alone, 12,800 women were be diagnosed with advanced cervical cancer in the U.S. and approximately 4,000 died of the disease. These women are predominantly poor and have reduced access to the health care system. Cervical cancer is primarily related to the sexual transmission of human papilloma virus (HPV). HPV has been shown to be associated with 95 percent of cervical epithelial neoplasms, and 50 percent of all-cervical cancer derives from a single strain, HPV-16. Current treatment modalities for advanced cervical cancer include chemotherapy and surgery, but morbidity and mortality remain unacceptably high. However, most cervical tumors continue to express HPV-related antigens thus providing a target for immunotherapeutic approaches. To address this challenge, Dr. Paterson's laboratory has developed a potent therapeutic vaccine vector, Listeria monocytogenes, which can target antigens to the immune system with the induction of strong cell mediated immunity. Using this approach to target the E7 antigen of HPV-16 in a mouse model, they have demonstrated that HPV-transformed macroscopic tumors can be cured. One drawback of this technology, however, has been the need to introduce antibiotic resistance genes into Listeria as a selection factor for transformation of the bacterial vector. Vectors containing these genes may not be suitable for human use because of concerns about spreading such resistance to other bacteria. Advaxis is working to commercialize these approaches. The work to be completed during this grant period will test the following hypothesis: Listeria monocytogenes, genetically engineered to express the E7 antigen in combination with certain bacterial proteins and rendered safe for human usage by attenuation and by removing antibiotic resistance genes, will show specific antitumor activity against HPV-transformed cells in vivo and ultimately in patients.
The specific aims of our work during this grant period are to (1) complete the work on the engineered bacterial vector needed for the clinical trial using a strain of Listeria that does not have antibiotic resistance genes; (2) retest the re-engineered vector in the mouse model for HPV transformed cancer; (3) determine biodistribution of the therapeutic, and (4) initiate toxicology testing in the mouse. The long-term goal of the current work is to advance this therapy into and through human clinical trials. This agent could become a useful therapy for cervical cancer, either as a primary therapy or as an adjunct to standard treatments. In addition, this technology can be applied to other cancers and infectious diseases, projects that are in preclinical development.
