Targeting sperm protein 17 for developing an immunotherapeutic treatment for ovarian cancer.

Abstract

INTRODUCTION: Ovarian Cancer (OC) is the leading cause of death from gynaecological malignancy. Immunotherapeutic strategies are less toxic and more specific than current treatments. Sperm protein (sp17) is a cancer-testes antigen that is aberrantly expressed in ovarian and other cancers, but is generally undetectable on normal tissues. This restricted expression pattern makes SP17 an attractive target for the development of novel immunotherapies for OC. METHODS: Using SP17 overlapping peptides as vaccine targets, adjuvanted with CpG or nanoparticles, we assessed the induction of immune responses in vivo (in mice); as well as the anti-tumor activity of anti-Sp17 antibodies in vitro using OC cell lines. The study was approved by the Alfred Medical Research and Education Precinct (AMREP) animal ethics committee. RESULTS: 1) We identified a highly immunogenic region (hSp17111-142) in the human Sp17 sequence which induces high levels of antibodies and IFN-γ producing T cells both in C57BL/6 and in C57BL/6-HLA-A2.1 transgenic mice when adjuvanted with CpG or nanoparticles. Furthermore, immunization of C57BL/6 mice with CpG-adjuvanted hSp17111-142 significantly prolonged survival in our model of disseminated ovarian carcinoma. 2) We mapped the immuno-dominant B and T cell epitope regions within the hSp17111-142, and identified a single immuno-dominant B cell (134-142 aa) epitope and two T helper 1 (Th1) cell epitopes (111-124 and 124-138 aa). Our recent studies show that anti-hSp17111-142 serum antibody can directly kill the OC tumor cell lines derived from either mouse or human origins in vitro. Sp17 expression is indispensable for tumor survival in vivo, and highly co-localized with 2 markers associated with both tumor recurrence and acquired chemoresistance. CONCLUSION: Our finding provides an opportunity to design an immunotherapeutic regiment targeting Sp17 as a novel immunotherapeutic treatment for OC - particularly for patients with recurrent or chemoresistant disease. This discovery has been submitted for an international PCT patent.