Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system

Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune s...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2014-11, Vol.74 (21), p.6260-6270
Hauptverfasser: Xu, Xin, Hegazy, Wael A H, Guo, Linjie, Gao, Xiuhua, Courtney, Amy N, Kurbanov, Suhrab, Liu, Daofeng, Tian, Gengwen, Manuel, Edwin R, Diamond, Don J, Hensel, Michael, Metelitsa, Leonid S
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container_end_page 6270
container_issue 21
container_start_page 6260
container_title Cancer research (Chicago, Ill.)
container_volume 74
creator Xu, Xin
Hegazy, Wael A H
Guo, Linjie
Gao, Xiuhua
Courtney, Amy N
Kurbanov, Suhrab
Liu, Daofeng
Tian, Gengwen
Manuel, Edwin R
Diamond, Don J
Hensel, Michael
Metelitsa, Leonid S
description Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines.
doi_str_mv 10.1158/0008-5472.CAN-14-1169
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However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. 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However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines.</abstract><cop>United States</cop><pmid>25213323</pmid><doi>10.1158/0008-5472.CAN-14-1169</doi><tpages>11</tpages></addata></record>
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subjects Animals
Antigen-Presenting Cells - immunology
Antigens, Neoplasm - administration & dosage
Bacterial Proteins - genetics
Cancer Vaccines - administration & dosage
Cancer Vaccines - immunology
CD8-Positive T-Lymphocytes - drug effects
CD8-Positive T-Lymphocytes - immunology
Humans
Membrane Proteins - genetics
Mice
Natural Killer T-Cells - immunology
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - prevention & control
Salmonella
Salmonella typhimurium - genetics
Salmonella typhimurium - immunology
Vaccines, Attenuated - administration & dosage
Vaccines, Attenuated - immunology
title Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system
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