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Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity
Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we asses...
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Published in: | The Journal of immunology (1950) 2002-05, Vol.168 (10), p.4914-4919 |
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container_title | The Journal of immunology (1950) |
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creator | Dredge, Keith Marriott, J. Blake Todryk, Stephen M Muller, George W Chen, Roger Stirling, David I Dalgleish, Angus G |
description | Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents. |
doi_str_mv | 10.4049/jimmunol.168.10.4914 |
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Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. 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Blake</creatorcontrib><creatorcontrib>Todryk, Stephen M</creatorcontrib><creatorcontrib>Muller, George W</creatorcontrib><creatorcontrib>Chen, Roger</creatorcontrib><creatorcontrib>Stirling, David I</creatorcontrib><creatorcontrib>Dalgleish, Angus G</creatorcontrib><title>Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. 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Blake ; Todryk, Stephen M ; Muller, George W ; Chen, Roger ; Stirling, David I ; Dalgleish, Angus G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-a047f3341db322758274ed09c26f2bbb8e85ebd46c43303382662e41046d8cf63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adjuvants, Immunologic - administration & dosage</topic><topic>Animals</topic><topic>Antigens, CD - biosynthesis</topic><topic>Antineoplastic Combined Chemotherapy Protocols - immunology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>B7-1 Antigen - biosynthesis</topic><topic>B7-2 Antigen</topic><topic>Cancer Vaccines - administration & dosage</topic><topic>Cancer Vaccines - immunology</topic><topic>Cells, Cultured</topic><topic>Coculture Techniques</topic><topic>Cytokines - biosynthesis</topic><topic>Growth Inhibitors - administration & dosage</topic><topic>Growth Inhibitors - immunology</topic><topic>Histocompatibility Antigens Class I - biosynthesis</topic><topic>Injections, Intraperitoneal</topic><topic>Injections, Subcutaneous</topic><topic>Interferon-gamma - biosynthesis</topic><topic>Melanoma, Experimental</topic><topic>Membrane Glycoproteins - biosynthesis</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation - immunology</topic><topic>Spleen - cytology</topic><topic>Spleen - immunology</topic><topic>Spleen - metabolism</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>Th1 Cells - immunology</topic><topic>Thalidomide - administration & dosage</topic><topic>Thalidomide - analogs & derivatives</topic><topic>Tumor Cells, Cultured - immunology</topic><topic>Tumor Cells, Cultured - metabolism</topic><topic>Tumor Cells, Cultured - pathology</topic><topic>Tumor Cells, Cultured - transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dredge, Keith</creatorcontrib><creatorcontrib>Marriott, J. Blake</creatorcontrib><creatorcontrib>Todryk, Stephen M</creatorcontrib><creatorcontrib>Muller, George W</creatorcontrib><creatorcontrib>Chen, Roger</creatorcontrib><creatorcontrib>Stirling, David I</creatorcontrib><creatorcontrib>Dalgleish, Angus G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dredge, Keith</au><au>Marriott, J. 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In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-gamma and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8(+) and CD4(+) splenocyte fractions from treated groups secreted increased IFN-gamma and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. 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subjects | Adjuvants, Immunologic - administration & dosage Animals Antigens, CD - biosynthesis Antineoplastic Combined Chemotherapy Protocols - immunology Antineoplastic Combined Chemotherapy Protocols - therapeutic use B7-1 Antigen - biosynthesis B7-2 Antigen Cancer Vaccines - administration & dosage Cancer Vaccines - immunology Cells, Cultured Coculture Techniques Cytokines - biosynthesis Growth Inhibitors - administration & dosage Growth Inhibitors - immunology Histocompatibility Antigens Class I - biosynthesis Injections, Intraperitoneal Injections, Subcutaneous Interferon-gamma - biosynthesis Melanoma, Experimental Membrane Glycoproteins - biosynthesis Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Neoplasm Transplantation - immunology Spleen - cytology Spleen - immunology Spleen - metabolism T-Lymphocyte Subsets - immunology Th1 Cells - immunology Thalidomide - administration & dosage Thalidomide - analogs & derivatives Tumor Cells, Cultured - immunology Tumor Cells, Cultured - metabolism Tumor Cells, Cultured - pathology Tumor Cells, Cultured - transplantation |
title | Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity |
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