HspE7 INFECTIOUS DISEASE VACCINE FOR THE TREATMENT OF CERVICAL CARCINOMA

What are the Etiologic Agents for Cervical Carcinoma? n Epidemiological studies suggest that 90% of all cervical carcinomas and their associated precursor lesions are caused by Human Papillomavirus (HPV) n Variety of immunological cofactors and molecular events must take place between when an HPV infection occurs and a cervical cancer or its precursor develops

What are the Risk Factors for Developing Cervical Carcinoma? n Number of sexual partners n young age at first intercourse n early age of parity n cigarette smoking

Human Papillomaviruses n 110 HPV types have been described n Not all HPVs have oncogenic potential n HPV 6, 11, 42, 43, 44 cause the lesions associated with low oncogenic-risk group (LSIL) n HPV 16, 18, 31, 33, 35 39, 45, 51, 52, 56, 58 form the lesions associated with high oncogenic-risk group (HSIL) n HPV 18 is associated with adenocarcinoma and small- cell neuroendocrine tumors

Natural History of HPV Infection n HPV is an obligatory intranuclear organism that must infect immature mitotically active cells in order to establish itself in the epithelium n targets the squamous-columnar junction of the cervix n referred to as a “wart” or condyloma acuminata n lesions may regress or progress to invasive carcinoma n Not uncommon for an epithelium to be infected by more than one HPV type, especially in low-risk group n High-risk group multiple HPV types are infrequent

The Interaction of the HPV Genome with its Host Cell n HPV infects mitotically active immature epithelial cells n Results in a latent infection where viral DNA resides in the host nucleus and replication is tied to the cell cycle n Latent Infections: may convert to a replicative infections the signal to initiate this conversion is not known can not be detected morphologically can be detected only by molecular techniques

HPV Replicative Infections n Unclear to amount of HPV virions that are produced and shed during replicative phase n Larger number of viral particles are found in increasing amounts as the cell matures n It is the mature epithelial cell that shows morphologic characteristics used in diagnostic cytology (Pap smear)

Conventional Detection Methods Papanicolaou smear (Pap) – clinician takes a cellular sample from the squamous-columnar junction of the cervix and puts it on a slide – cytology lab stains and examines the specimen under the microscope for cellular abnormalities

Condyloma Acuminata

Morphologic Features of HPV

CIN I

CIN II & CIN III

CIS

Squamous Cell Carcinoma

Endocervical Adenocarcinoma

Small Cell Carcinoma

Molecular Events of HPV Oncogenesis n HPV types in high oncogenic risk groups produce E6 & E7 proteins that transform normal cells to neoplastic cells n E6 & E7 proteins deregulate the normal process of mitotic division by interfering with proteins of the normal feedback loops of cell division n E6-encoded protein binds to p53 (tumor suppressor) causing its inactivation and increasing its rate of degradation in the E/6p53 protein complex n E7 binds to the cyclin Ap107 protein and the retinoblastoma gene product, p105RB

HPV Oncogenesis n This neoplastic transformation is accompanied by mutations in 5 or more key mitotic regulatory proteins (p53, retinoblastoma, cyclin, etc.) n When cells are allowed to complete repeated mitotic cycles with mutations intact, there is a gradual accumulation of mutated genes n When a sufficient number of alterations in regulatory sequences have accumulated and an insufficient number of redundant regulatory pathways survive, the cell will be transformed neoplastically

Conventional Treatment n Cold cautery (liquid nitrogen freezing of tissue) n Hot cautery (burning of tissue) n Laser n Conventional surgery n Chemicals applied directly podophyllin trichloroacetic acid

New Treatment for Cervical Carcinoma Oncocine HspE7 n Developed by StressGen Biotechnologies Corp. n Therapeutic vaccine designed to treat patients who have cervical carcinoma n preclinical studies have shown complete regression of large existing tumors and protection against reoccurrence n Phase I clinical trial will treat patients with CIN II/III lesions to determine if HspE7 can be safely tolerated

What is Oncocine HspE7 n It is a recombinant protein composed of the M. bovis BCG stress protein 65 and the E7 protein from HPV 16 n Therapy is based on the use of stress proteins and stress protein genes to stimulate the body’s own immune defenses to fight disease

How does HspE7 work? n E7 protein is responsible for the transformation of HPV infected cells in to cancer cells n Demonstrated that foreign stress proteins(p65), fused to a wide variety of antigens(E7), can generate stronger T cell & B cell immune response n E7 protein is continuously expressed in cervical cancer cells, making it an ideal target for StressGen’s technology

Conclusion n Estimated between 300,000 and 1.5 million women in the US are diagnosed annually with HPV-induced abnormal cervical epithelial cells n Current treatment is not always effective n StressGen’s approach has the potential to immunologically target virally transformed cells specifically, reducing recurrence and the need for surgery

FUTURE TRENDS n If HPV vaccines are successful, we should see a marked decrease in the incidence of CIN and cervical cancers n A vaccine directed against HPV 16 alone would save the lives of 225,000 women yearly worldwide n A vaccine directed against HPV 16 and HPV 18 would decrease the incidence most cervical carcinomas