Treatment and identification of human papillomavirus (HPV) induced cervical precancer costs four to six billion dollars annually in the U.S. Currently, treatment of high-grade neoplasia is limited to surgical procedures that require expertise to perform. Both the cost of treatment and the magnitude of women impacted by HPV induced disease underscores the need for effective alternative therapies to cut costs and increase worldwide availability of treatment. Animal models and human clinical trials suggest that regression of HPV 16 positive lesions can be induced by immunotherapy using either T cell epitopes from HPV16 early protein E7 or by vaccinating with whole E7 protein. In this proposed trial, efficacy of using HSP-E7 (SGN-00101), a fusion protein linking the M. bovis BCG heat shock protein 65 (HSP65) to the early protein E7 of HPV type 16 will be tested for the treatment of cervical intraepithelial lesions II/III (CIN II/III). HSP65 is a mycobacterial heat shock protein component in the TB vaccine approved for human use. E7, the tumor antigen of HPV is expressed exclusively in HPV infected cells. HSP65 functions as a potent adjuvant for T cell responses. Combined these proteins have been shown to induce HPV16 E7 cytotoxic T cells (CTLs).We hypothesize that HSP-E7, when administered by subcutaneous route, will induce specific CTLs that will migrate to the genital tract and initiate regression of CIN II/III lesions without inducing systemic toxicities. To test this hypothesis we propose a Phase II study conducted in female subjects with biopsy proven, measurable, HPV16 positive, CIN II/III. Eligible patients will receive either a 500mcg dose of HSP-E7 or a placebo once a month for three months. The patients will be monitored monthly and followed for a total of six months after the first injection. At the final visit all patients will have a LEEP excision and the study endpoint will be defined based on the histology of the LEEP specimen. The study will accomplish the following aims: 1. Determine the efficacy of HSP-E7 for induction of a complete response defined as total histologic regression of CIN II/III and return to normal histology in HSP-E7 immunized women compared to a placebo controlled group; and 2. Correlate clinical response as defined by histologic demonstration of lesion regression with innovative surrogate markers of vaccine efficacy. Spectroscopic changes in the epithelium, development of HPV specific mucosal and systemic T cell responses and levels of HPV16 E2 specific antibody in cervical secretions will be evaluated as potential correlates of response.
| Butler, Jill S; Zurita-Lopez, Cecilia I; Clarke, Steven G et al. (2011) Protein-arginine methyltransferase 1 (PRMT1) methylates Ash2L, a shared component of mammalian histone H3K4 methyltransferase complexes. J Biol Chem 286:12234-44 |
