Cancer Immunity 6 Suppl 1:9 (2006)

In vivo antigen delivery by a Salmonella type III secretion system for therapeutic cancer vaccine development

Jorge E. Galán^1*, Hiroyoshi Nishikawa², Gabriel Briones¹, Sacha Gnjatic², Gerd Ritter², and Lloyd J. Old²

¹Yale University School of Medicine, New Haven, CT
²Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY
^*Presenting author

Abstract

Bacterial vectors offer many advantages over other antigen delivery systems for the construction of cancer vaccines because they are usually endowed with the ability to potently stimulate the innate immune system (1). This is particularly the case for Salmonella typhimurium, which has been extensively used as an antigen delivery vector to construct vaccines against various infectious diseases (2). We have recently developed a system that significantly improves the utility of Salmonella as an antigen delivery vehicle (3, 4). This system is based on the use of a specialized protein secretion apparatus (termed type III) that is normally utilized by Salmonella to deliver effector bacterial proteins into the extracellular medium as well as into the cytosol of infected cells (5). We have adapted this system to deliver heterologous proteins into class I- and class-II antigen presenting compartments and found that antigens delivered by this system stimulate strong immune responses both in vivo and in vitro. We have engineered a Salmonella typhimurium vaccine strain that delivers the NY-ESO-1 tumor antigen through its type III protein secretion system. Sal-NY-ESO-1 efficiently elicited NY-ESO-1-specific CD8+ and CD4+ T cell responses in vitro. Oral administration of Sal-NY-ESO-1 to mice resulted in the regression of established NY-ESO-1-expressing tumors. Tumor regression was significantly accelerated in NY-ESO-1 DNA-primed animals. Epitope spreading to at least two tumor antigens not contained in the vaccine was observed in vaccinated animals. We propose that tumor-antigen delivery through the Salmonella typhimurium type III secretion system constitutes a promising novel strategy for cancer vaccine development.

References

1. Chabalgoity JA, Dougan G, Mastroeni P, Aspinall RJ. Live bacteria as the basis for immunotherapies against cancer. Expert Rev Vaccines 2002; 1: 495-505. (PMID: 12901588)

2. Curtiss R 3rd, Kelly SM, Tinge SA, Tacket CO, Levine MM, Srinivasan J, Koopman M. Recombinant Salmonella vectors in vaccine development. Dev Biol Stand 1994; 82: 23-33. (PMID: 7958478)

3. Rüssmann H, Shams H, Poblete F, Fu Y, Galán JE, Donis RO. Delivery of epitopes by the Salmonella type III secretion system for vaccine development. Science 1998; 281: 565-8. (PMID: 9677200)

4. Evans DT, Chen LM, Gillis J, Lin KC, Harty B, Mazzara GP, Donis RO, Mansfield KG, Lifson JD, Desrosiers RC, Galan JE, Johnson RP. Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system. J Virol 2003; 77: 2400-9. (PMID: 12551977)

5. Galán JE, Collmer C. Type III secretion machines: bacterial devices for protein delivery into host cells. Science 1999; 284: 1322-8. (PMID: 10334981)