620. Liposome-Based Therapeutic Vaccine for Cervical Cancer

Abstract

Top of pageAbstract Cervical cancer is the second most common cancer among women worldwide. More than 99% of cervical cancers contain human papillomavirus (HPV) DNA while HPV type 16 is the most common subtype and is associated with 50% of cervical cancer cases. Preventive vaccine against HPV infection is already available on market, however, there is not yet a therapeutic vaccine thus far for replacing of the traumatic surgery on patients with cervical carcinoma. The E7 viral protein of HPV16, which is continuously expressed in cervical cancer cells and pre-cancerous lesions, is also a unique antigen for targeting cervical tumor and can be used a potential therapeutic strategy. Previous work in our lab has led to the development of a liposome-based non-viral vaccine delivery system, LPD. The nanoparticle LPD is self-assembled from cationic lipid, protamine and plasmid DNA. We have demonstrated that LPD formulated with a peptide epitope from the HPV16 E7 protein can be taken up by the dendritic cells and the vaccine induces both preventive as well as therapeutic activity against TC-1, a murine cancer cell line which is HPV16-DNA positive and a model for human cervical cancer. In order to study the mechanism how LPD plays a novel adjuvant for stimulating both humoral and cellular immune responses, we have found that DOTAP liposome can stimulate murine dendritic cells (professional antigen presenting cells) toward the expression of costimulatory molecules, i.e. CD80 and CD86. The results were also confirmed in human DC-like cell line, KG-1. Surface markers on KG-1 for identifying DC lineage, i.e. CD11c CD80, CD83 and CD86 were increased via DOTAP liposome stimulation and the amount of the increase was DOTAP dose-dependent. Since high dose of liposome has been reported to cause possible unwanted toxicity, we have tested serum TNF-alpha cytokine secretion from the mice received our LPD/E7 formulation and we found that very low or not detectable amount of TNF-alpha were measured after mice received s.c. injection. In order to optimize our vaccine formulation, we have found that the reduced amount of liposome can also elicit efficient activity and provide therapeutic effect on tumor-bearing mice. All the results obtained from mouse system are being confirmed on human primary DC isolated from human peripheral mononuclear cells (PBMC). Success of these experiments will constitute a strong rationale for a future phase I clinical trial. Supported by Mary Kay Ash Charitable Foundation.