Development of an Escherichia coli Expressing Listeriolysin-O Vaccine Against Wilms Tumor Gene 1-expressing Tumors

Abstract

Through their ability to induce cytotoxic T-lymphocytes and inhibit Foxp3 T-regulatory cells, Escherichia coli expressing listeriolysin-O (LLO) and a model tumor antigen have been shown to exert strong antitumor activity. The aim of this study is to extend these observations to a self-protein and clinically relevant tumor antigen associated with most types of adult leukemia: Wilms tumor gene 1 (WT1). We demonstrate that an E. coli coexpressing LLO and WT1 is capable of inducing a strong antitumor effect against WT1-expressing tumors in vivo through its ability to induce cytotoxic T-lymphocytes and inhibit the function of Foxp3 T-regulatory cells. Furthermore, we have characterized the immunodominant epitope involved in this effect (NAPYLPSCL) and demonstrated that coinjection of NAPYLPSCL with E. coli-LLO resulted in an antitumor effect largely equivalent to that obtained with E. coli-LLO/WT1. Our data demonstrate that the results obtained with a clinically irrelevant model tumor antigen remain valid with a "real" tumor antigen and that the adjuvant properties of the E. coli-LLO vaccine can be exploited in conjunction with peptides. The results obtained in this study will facilitate the translation of this work to human studies by combining antigenic motifs relevant to specific human leukocyte antigen haplotypes with the adjuvant effect of E. coli-LLO.