TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CA...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2018-01, Vol.78 (2), p.489-500 |
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| creator | Byrd, Tiara T Fousek, Kristen Pignata, Antonella Szot, Christopher Samaha, Heba Seaman, Steven Dobrolecki, Lacey Salsman, Vita S Oo, Htoo Zarni Bielamowicz, Kevin Landi, Daniel Rainusso, Nino Hicks, John Powell, Suzanne Baker, Matthew L Wels, Winfried S Koch, Joachim Sorensen, Poul H Deneen, Benjamin Ellis, Matthew J Lewis, Michael T Hegde, Meenakshi Fletcher, Bradley S St Croix, Brad Ahmed, Nabil |
| description | Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8
TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.
These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature.
. |
| doi_str_mv | 10.1158/0008-5472.CAN-16-1911 |
| format | Article |
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TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.
These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature.
.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-16-1911</identifier><identifier>PMID: 29183891</identifier><language>eng</language><publisher>United States: American Association for Cancer Research, Inc</publisher><subject>Adoptive transfer ; Animals ; Antigens ; Apoptosis ; Biomarkers, Tumor ; Breast cancer ; Case-Control Studies ; Cell Proliferation ; Cell- and Tissue-Based Therapy ; Colon ; Cytokines ; Endothelial cells ; Endothelium ; Female ; Follow-Up Studies ; Humans ; Immunostimulation ; Immunotherapy ; Lung Neoplasms - immunology ; Lung Neoplasms - secondary ; Lung Neoplasms - therapy ; Lungs ; Lymphocytes ; Lymphocytes T ; Metastases ; Mice ; Microfilament Proteins ; Neoplasm Proteins - metabolism ; Prognosis ; Receptors, Antigen, T-Cell - metabolism ; Receptors, Cell Surface - metabolism ; Survival Rate ; T-Lymphocytes - immunology ; T-Lymphocytes - transplantation ; Triple Negative Breast Neoplasms - immunology ; Triple Negative Breast Neoplasms - pathology ; Triple Negative Breast Neoplasms - therapy ; Tumor cells ; Tumor Cells, Cultured ; Tumors ; Vascularization ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cancer research (Chicago, Ill.), 2018-01, Vol.78 (2), p.489-500</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research, Inc. Jan 15, 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c543t-e332f71ec00de6ecdd47855a28e6c8d7c357d2daedde506a7e7642a44a0749d23</citedby><cites>FETCH-LOGICAL-c543t-e332f71ec00de6ecdd47855a28e6c8d7c357d2daedde506a7e7642a44a0749d23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,3360,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29183891$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Byrd, Tiara T</creatorcontrib><creatorcontrib>Fousek, Kristen</creatorcontrib><creatorcontrib>Pignata, Antonella</creatorcontrib><creatorcontrib>Szot, Christopher</creatorcontrib><creatorcontrib>Samaha, Heba</creatorcontrib><creatorcontrib>Seaman, Steven</creatorcontrib><creatorcontrib>Dobrolecki, Lacey</creatorcontrib><creatorcontrib>Salsman, Vita S</creatorcontrib><creatorcontrib>Oo, Htoo Zarni</creatorcontrib><creatorcontrib>Bielamowicz, Kevin</creatorcontrib><creatorcontrib>Landi, Daniel</creatorcontrib><creatorcontrib>Rainusso, Nino</creatorcontrib><creatorcontrib>Hicks, John</creatorcontrib><creatorcontrib>Powell, Suzanne</creatorcontrib><creatorcontrib>Baker, Matthew L</creatorcontrib><creatorcontrib>Wels, Winfried S</creatorcontrib><creatorcontrib>Koch, Joachim</creatorcontrib><creatorcontrib>Sorensen, Poul H</creatorcontrib><creatorcontrib>Deneen, Benjamin</creatorcontrib><creatorcontrib>Ellis, Matthew J</creatorcontrib><creatorcontrib>Lewis, Michael T</creatorcontrib><creatorcontrib>Hegde, Meenakshi</creatorcontrib><creatorcontrib>Fletcher, Bradley S</creatorcontrib><creatorcontrib>St Croix, Brad</creatorcontrib><creatorcontrib>Ahmed, Nabil</creatorcontrib><title>TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8
TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.
These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature.
.</description><subject>Adoptive transfer</subject><subject>Animals</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Biomarkers, Tumor</subject><subject>Breast cancer</subject><subject>Case-Control Studies</subject><subject>Cell Proliferation</subject><subject>Cell- and Tissue-Based Therapy</subject><subject>Colon</subject><subject>Cytokines</subject><subject>Endothelial cells</subject><subject>Endothelium</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Immunostimulation</subject><subject>Immunotherapy</subject><subject>Lung Neoplasms - immunology</subject><subject>Lung Neoplasms - secondary</subject><subject>Lung Neoplasms - therapy</subject><subject>Lungs</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Metastases</subject><subject>Mice</subject><subject>Microfilament Proteins</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Prognosis</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Survival Rate</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - transplantation</subject><subject>Triple Negative Breast Neoplasms - immunology</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Triple Negative Breast Neoplasms - therapy</subject><subject>Tumor cells</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Vascularization</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkV1LHDEUhoNYdKv9CZaAN72JJpl8zU1hO9gP0BV0BO9CTM6sI7Mz02RW8N83g3ZphUAIec7LeXkQOmH0jDFpzimlhkih-Vm1XBGmCCsZ20MLJgtDtBByHy12zCH6mNJTfkpG5QE65CUzhSnZAt3XF1fmfLmq728YuR3Bt03rcbW8wTWuoOsSdvng2sU1TBBw_QjRjS-4GSKuYzt2QFawdlP7DPhbBJcmXLneQzxGHxrXJfj0dh-hu-8XdfWTXF7_-FUtL4mXopgIFAVvNANPaQAFPgShjZSOG1DeBO0LqQMPDkIASZXToJXgTghHtSgDL47Q19fccfuwgeChn6Lr7BjbjYsvdnCt_f-nbx_teni2UmtmqMoBX94C4vB7C2mymzb5XN31MGyTZaWmPKNGZ_T0Hfo0bGOf61lOqTJaKzUHylfKxyGlCM1uGUbt7M7OXuzsxWZ3lik7u8tzn_9tspv6K6v4A-L4k5A</recordid><startdate>20180115</startdate><enddate>20180115</enddate><creator>Byrd, Tiara T</creator><creator>Fousek, Kristen</creator><creator>Pignata, Antonella</creator><creator>Szot, Christopher</creator><creator>Samaha, Heba</creator><creator>Seaman, Steven</creator><creator>Dobrolecki, Lacey</creator><creator>Salsman, Vita S</creator><creator>Oo, Htoo Zarni</creator><creator>Bielamowicz, Kevin</creator><creator>Landi, Daniel</creator><creator>Rainusso, Nino</creator><creator>Hicks, John</creator><creator>Powell, Suzanne</creator><creator>Baker, Matthew L</creator><creator>Wels, Winfried S</creator><creator>Koch, Joachim</creator><creator>Sorensen, Poul H</creator><creator>Deneen, Benjamin</creator><creator>Ellis, Matthew J</creator><creator>Lewis, Michael T</creator><creator>Hegde, Meenakshi</creator><creator>Fletcher, Bradley S</creator><creator>St Croix, Brad</creator><creator>Ahmed, Nabil</creator><general>American Association for Cancer Research, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180115</creationdate><title>TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer</title><author>Byrd, Tiara T ; Fousek, Kristen ; Pignata, Antonella ; Szot, Christopher ; Samaha, Heba ; Seaman, Steven ; Dobrolecki, Lacey ; Salsman, Vita S ; Oo, Htoo Zarni ; Bielamowicz, Kevin ; Landi, Daniel ; Rainusso, Nino ; Hicks, John ; Powell, Suzanne ; Baker, Matthew L ; Wels, Winfried S ; Koch, Joachim ; Sorensen, Poul H ; Deneen, Benjamin ; Ellis, Matthew J ; Lewis, Michael T ; Hegde, Meenakshi ; Fletcher, Bradley S ; St Croix, Brad ; Ahmed, Nabil</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c543t-e332f71ec00de6ecdd47855a28e6c8d7c357d2daedde506a7e7642a44a0749d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adoptive transfer</topic><topic>Animals</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Biomarkers, Tumor</topic><topic>Breast cancer</topic><topic>Case-Control Studies</topic><topic>Cell Proliferation</topic><topic>Cell- and Tissue-Based Therapy</topic><topic>Colon</topic><topic>Cytokines</topic><topic>Endothelial cells</topic><topic>Endothelium</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Immunostimulation</topic><topic>Immunotherapy</topic><topic>Lung Neoplasms - immunology</topic><topic>Lung Neoplasms - secondary</topic><topic>Lung Neoplasms - therapy</topic><topic>Lungs</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Metastases</topic><topic>Mice</topic><topic>Microfilament Proteins</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Prognosis</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Survival Rate</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - transplantation</topic><topic>Triple Negative Breast Neoplasms - immunology</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Triple Negative Breast Neoplasms - therapy</topic><topic>Tumor cells</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><topic>Vascularization</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Byrd, Tiara T</creatorcontrib><creatorcontrib>Fousek, Kristen</creatorcontrib><creatorcontrib>Pignata, Antonella</creatorcontrib><creatorcontrib>Szot, Christopher</creatorcontrib><creatorcontrib>Samaha, Heba</creatorcontrib><creatorcontrib>Seaman, Steven</creatorcontrib><creatorcontrib>Dobrolecki, Lacey</creatorcontrib><creatorcontrib>Salsman, Vita S</creatorcontrib><creatorcontrib>Oo, Htoo Zarni</creatorcontrib><creatorcontrib>Bielamowicz, Kevin</creatorcontrib><creatorcontrib>Landi, Daniel</creatorcontrib><creatorcontrib>Rainusso, Nino</creatorcontrib><creatorcontrib>Hicks, John</creatorcontrib><creatorcontrib>Powell, Suzanne</creatorcontrib><creatorcontrib>Baker, Matthew L</creatorcontrib><creatorcontrib>Wels, Winfried S</creatorcontrib><creatorcontrib>Koch, Joachim</creatorcontrib><creatorcontrib>Sorensen, Poul H</creatorcontrib><creatorcontrib>Deneen, Benjamin</creatorcontrib><creatorcontrib>Ellis, Matthew J</creatorcontrib><creatorcontrib>Lewis, Michael T</creatorcontrib><creatorcontrib>Hegde, Meenakshi</creatorcontrib><creatorcontrib>Fletcher, Bradley S</creatorcontrib><creatorcontrib>St Croix, Brad</creatorcontrib><creatorcontrib>Ahmed, Nabil</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>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Byrd, Tiara T</au><au>Fousek, Kristen</au><au>Pignata, Antonella</au><au>Szot, Christopher</au><au>Samaha, Heba</au><au>Seaman, Steven</au><au>Dobrolecki, Lacey</au><au>Salsman, Vita S</au><au>Oo, Htoo Zarni</au><au>Bielamowicz, Kevin</au><au>Landi, Daniel</au><au>Rainusso, Nino</au><au>Hicks, John</au><au>Powell, Suzanne</au><au>Baker, Matthew L</au><au>Wels, Winfried S</au><au>Koch, Joachim</au><au>Sorensen, Poul H</au><au>Deneen, Benjamin</au><au>Ellis, Matthew J</au><au>Lewis, Michael T</au><au>Hegde, Meenakshi</au><au>Fletcher, Bradley S</au><au>St Croix, Brad</au><au>Ahmed, Nabil</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2018-01-15</date><risdate>2018</risdate><volume>78</volume><issue>2</issue><spage>489</spage><epage>500</epage><pages>489-500</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Triple-negative breast cancer (TNBC) is an aggressive disease lacking targeted therapy. In this study, we developed a CAR T cell-based immunotherapeutic strategy to target TEM8, a marker initially defined on endothelial cells in colon tumors that was discovered recently to be upregulated in TNBC. CAR T cells were developed that upon specific recognition of TEM8 secreted immunostimulatory cytokines and killed tumor endothelial cells as well as TEM8-positive TNBC cells. Notably, the TEM8 CAR T cells targeted breast cancer stem-like cells, offsetting the formation of mammospheres relative to nontransduced T cells. Adoptive transfer of TEM8 CAR T cells induced regression of established, localized patient-derived xenograft tumors, as well as lung metastatic TNBC cell line-derived xenograft tumors, by both killing TEM8
TNBC tumor cells and targeting the tumor endothelium to block tumor neovascularization. Our findings offer a preclinical proof of concept for immunotherapeutic targeting of TEM8 as a strategy to treat TNBC.
These findings offer a preclinical proof of concept for immunotherapeutic targeting of an endothelial antigen that is overexpressed in triple-negative breast cancer and the associated tumor vasculature.
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| ispartof | Cancer research (Chicago, Ill.), 2018-01, Vol.78 (2), p.489-500 |
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| source | MEDLINE; American Association for Cancer Research; EZB Electronic Journals Library |
| subjects | Adoptive transfer Animals Antigens Apoptosis Biomarkers, Tumor Breast cancer Case-Control Studies Cell Proliferation Cell- and Tissue-Based Therapy Colon Cytokines Endothelial cells Endothelium Female Follow-Up Studies Humans Immunostimulation Immunotherapy Lung Neoplasms - immunology Lung Neoplasms - secondary Lung Neoplasms - therapy Lungs Lymphocytes Lymphocytes T Metastases Mice Microfilament Proteins Neoplasm Proteins - metabolism Prognosis Receptors, Antigen, T-Cell - metabolism Receptors, Cell Surface - metabolism Survival Rate T-Lymphocytes - immunology T-Lymphocytes - transplantation Triple Negative Breast Neoplasms - immunology Triple Negative Breast Neoplasms - pathology Triple Negative Breast Neoplasms - therapy Tumor cells Tumor Cells, Cultured Tumors Vascularization Xenograft Model Antitumor Assays Xenografts |
| title | TEM8/ANTXR1-Specific CAR T Cells as a Targeted Therapy for Triple-Negative Breast Cancer |
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