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

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.