In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines
Hiroyoshi Nishikawa, … , Jorge E. Galán, Sacha Gnjatic
Hiroyoshi Nishikawa, … , Jorge E. Galán, Sacha Gnjatic
Published July 3, 2006
Citation Information: J Clin Invest. 2006;116(7):1946-1954. https://doi.org/10.1172/JCI28045.
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Research Article Vaccines

In vivo antigen delivery by a Salmonella typhimurium type III secretion system for therapeutic cancer vaccines

Abstract

Bacterial vectors may offer many advantages over other antigen delivery systems for cancer vaccines. We engineered a Salmonella typhimuriumvaccine strain to deliver the NY-ESO-1 tumor antigen (S. typhimurium–NY-ESO-1) through a type III protein secretion system. The S. typhimurium–NY-ESO-1 construct elicited NY-ESO-1–specific CD8+ and CD4+ T cells from peripheral blood lymphocytes ofcancer patients in vitro. Oral administration of S. typhimurium–NY-ESO-1 to mice resulted in the regression of established NY-ESO-1–expressing tumors. Intratumoral inoculation of S. typhimurium–NY-ESO-1 to NY-ESO-1–negative tumors resulted in delivery of antigen in vivo and led to tumor regression in the presence of preexisting NY-ESO-1–specific CD8+ T cells. Specific T cell responses against at least 2 unrelated tumor antigens not contained in the vaccine were observed, demonstrating epitope spreading. We propose that antigen delivery through the S. typhimuriumtype III secretion system is a promising novel strategy for cancer vaccine development.

Authors

Hiroyoshi Nishikawa, Eiichi Sato, Gabriel Briones, Li-Mei Chen, Mitsutoshi Matsuo, Yasuhiro Nagata, Gerd Ritter, Elke Jäger, Hideki Nomura, Shigeto Kondo, Isao Tawara, Takuma Kato, Hiroshi Shiku, Lloyd J. Old, Jorge E. Galán, Sacha Gnjatic

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Figure 6

Local tumor antigen delivery byS. typhimurium type III secretion system causes regression of tumors in mice by epitope spreading.

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Local tumor antigen delivery byS. typhimurium ...
(A) BALB/c mice were immunized twice at 2-week intervals with plasmids encoding NY-ESO-1 or control vector by gene gun. These mice were inoculated with 2 × 106 CMS5a-HE tumor cells (NY-ESO-1–negative), and tumor growth was analyzed 3 times per week. After 7 days, injection of 0.5–1 × 106 CFU of S. typhimurium–NY-ESO-1 or of the control strain at the tumor site was performed. Some groups of mice were also injected intravenously with anti-CD4 or anti-CD8 mAb or control Ab in the form of 25-μl ascites every 5 days. Arrows indicate time points of S. typhimurium administration. Each line represents the tumor growth of an individual mouse. Tumor size was calculated as longitudinal diameter (mm) × horizontal diameter (mm). (B) CD8+ T cells were purified from spleens from control vector– or NY-ESO-1–preimmunized mice bearing CMS5a-HE, either untreated or treated with S. typhimurium–NY-ESO-1 or the control strain, and analyzed for the number of specific IFN-γ–producing cells by ELISPOT assay. Data are mean ± SD. Experiments were performed independently at least twice with similar results.