Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen
CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, ter...
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| Veröffentlicht in: | Leukemia 2017-08, Vol.31 (8), p.1788-1797 |
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| creator | Rafiq, S Purdon, T J Daniyan, A F Koneru, M Dao, T Liu, C Scheinberg, D A Brentjens, R J |
| description | CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This
in vivo
functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy. |
| doi_str_mv | 10.1038/leu.2016.373 |
| format | Article |
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in vivo
functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2016.373</identifier><identifier>PMID: 27924074</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/109 ; 13/21 ; 13/31 ; 42 ; 42/34 ; 42/44 ; 631/250/251 ; 631/67/1059/2325 ; 64/60 ; 82 ; Acute lymphocytic leukemia ; Animals ; Antigen (tumor-associated) ; Antigens ; Automobiles ; Cancer Research ; Care and treatment ; CD19 antigen ; Cell Line ; Chimeric antigen receptors ; Critical Care Medicine ; Female ; Hematology ; Histocompatibility antigen HLA ; HLA-A Antigens - analysis ; Humans ; Immunotherapy ; Intensive ; Interleukin-12 - biosynthesis ; Internal Medicine ; Intracellular ; Leukemia ; Leukemia - therapy ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine & Public Health ; Mice ; Oncology ; original-article ; Ovarian cancer ; Ovarian Neoplasms - therapy ; Receptors, Antigen, T-Cell - immunology ; Recombinant Fusion Proteins - immunology ; Retroviridae - genetics ; T cell antigen receptors ; T cell receptors ; Therapy ; Transcriptome ; Tumors ; WT1 protein ; WT1 Proteins - analysis ; WT1 Proteins - immunology</subject><ispartof>Leukemia, 2017-08, Vol.31 (8), p.1788-1797</ispartof><rights>The Author(s) 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c548t-3399a93d0679c60dd55173455c9b0833fc8ea62b107bf011241e8b52aace3f573</citedby><cites>FETCH-LOGICAL-c548t-3399a93d0679c60dd55173455c9b0833fc8ea62b107bf011241e8b52aace3f573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2016.373$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2016.373$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27924074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rafiq, S</creatorcontrib><creatorcontrib>Purdon, T J</creatorcontrib><creatorcontrib>Daniyan, A F</creatorcontrib><creatorcontrib>Koneru, M</creatorcontrib><creatorcontrib>Dao, T</creatorcontrib><creatorcontrib>Liu, C</creatorcontrib><creatorcontrib>Scheinberg, D A</creatorcontrib><creatorcontrib>Brentjens, R J</creatorcontrib><title>Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This
in vivo
functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.</description><subject>13</subject><subject>13/109</subject><subject>13/21</subject><subject>13/31</subject><subject>42</subject><subject>42/34</subject><subject>42/44</subject><subject>631/250/251</subject><subject>631/67/1059/2325</subject><subject>64/60</subject><subject>82</subject><subject>Acute lymphocytic leukemia</subject><subject>Animals</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Automobiles</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>CD19 antigen</subject><subject>Cell Line</subject><subject>Chimeric antigen receptors</subject><subject>Critical Care Medicine</subject><subject>Female</subject><subject>Hematology</subject><subject>Histocompatibility antigen HLA</subject><subject>HLA-A Antigens - analysis</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Intensive</subject><subject>Interleukin-12 - biosynthesis</subject><subject>Internal Medicine</subject><subject>Intracellular</subject><subject>Leukemia</subject><subject>Leukemia - therapy</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Oncology</subject><subject>original-article</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - therapy</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Recombinant Fusion Proteins - immunology</subject><subject>Retroviridae - genetics</subject><subject>T cell antigen receptors</subject><subject>T cell receptors</subject><subject>Therapy</subject><subject>Transcriptome</subject><subject>Tumors</subject><subject>WT1 protein</subject><subject>WT1 Proteins - analysis</subject><subject>WT1 Proteins - immunology</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptks1r3DAQxUVpabbb3nouhkLpod5KlmVJl0AI6QcEctnSo5Dt8a6CbW0luSX96zNmk-1uCT7IzPvNs2f0CHnL6IpRrj73MK0KyqoVl_wZWbBSVrkQgj0nC6qUzCtdlGfkVYy3lM5i9ZKcFRKLVJYLcnezS25wf6HN1nkDfZ8FaGCXfMgHrDdZs3UDBHyxY3IbGA96ts5mPmatw1JCg-T_2IDHFjI3pmBneeptyH66fojZehqwiz0avSYvOttHePNwLsmPL1fry2_59c3X75cX13kjSpVyzrW2mre0krqpaNviaJKXQjS6porzrlFgq6JmVNYdZawoGahaFBY_zzsh-ZKc7313Uz1A28D8a73ZBTfYcGe8deZUGd3WbPxvI0otqoKjwccHg-B_TRCTGVycZ7Mj-CkapspKMq2QXZL3_6G3fgojjmeYLgRTmpb0H7WxPRg3dn5e1mxqLkqtJV6TYkitnqDwaQHvxY_QOayfNHw4atiC7dM2-n5Kzo_xFPy0B5vgYwzQHZbBqJkzZTBTZs6UwUwh_u54gQf4MUQI5HsgojRuIBxN_ZThPe7f1a4</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Rafiq, S</creator><creator>Purdon, T J</creator><creator>Daniyan, A F</creator><creator>Koneru, M</creator><creator>Dao, T</creator><creator>Liu, C</creator><creator>Scheinberg, D A</creator><creator>Brentjens, R J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170801</creationdate><title>Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen</title><author>Rafiq, S ; Purdon, T J ; Daniyan, A F ; Koneru, M ; Dao, T ; Liu, C ; Scheinberg, D A ; Brentjens, R J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c548t-3399a93d0679c60dd55173455c9b0833fc8ea62b107bf011241e8b52aace3f573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13</topic><topic>13/109</topic><topic>13/21</topic><topic>13/31</topic><topic>42</topic><topic>42/34</topic><topic>42/44</topic><topic>631/250/251</topic><topic>631/67/1059/2325</topic><topic>64/60</topic><topic>82</topic><topic>Acute lymphocytic leukemia</topic><topic>Animals</topic><topic>Antigen (tumor-associated)</topic><topic>Antigens</topic><topic>Automobiles</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>CD19 antigen</topic><topic>Cell Line</topic><topic>Chimeric antigen receptors</topic><topic>Critical Care Medicine</topic><topic>Female</topic><topic>Hematology</topic><topic>Histocompatibility antigen HLA</topic><topic>HLA-A Antigens - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rafiq, S</au><au>Purdon, T J</au><au>Daniyan, A F</au><au>Koneru, M</au><au>Dao, T</au><au>Liu, C</au><au>Scheinberg, D A</au><au>Brentjens, R J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>31</volume><issue>8</issue><spage>1788</spage><epage>1797</epage><pages>1788-1797</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>CD19-directed chimeric antigen receptor (CAR) T cells are clinically effective in a limited set of leukemia patients. However, CAR T-cell therapy thus far has been largely restricted to targeting extracellular tumor-associated antigens (TAA). Herein, we report a T-cell receptor-mimic (TCRm) CAR, termed WT1-28z, that is reactive to a peptide portion of the intracellular onco-protein Wilms Tumor 1(WT1), as it is expressed on the surface of the tumor cell in the context of HLA-A*02:01. T cells modified to express WT1-28z specifically targeted and lysed HLA-A*02:01+ WT1+ tumors and enhanced survival of mice engrafted with HLA-A*02:01+, WT1+ leukemia or ovarian tumors. This
in vivo
functional validation of TCRm CAR T cells provides the proof-of-concept necessary to expand the range of TAA that can be effectively targeted for immunotherapy to include attractive intracellular targets, and may hold great potential to expand on the success of CAR T-cell therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27924074</pmid><doi>10.1038/leu.2016.373</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/109 13/21 13/31 42 42/34 42/44 631/250/251 631/67/1059/2325 64/60 82 Acute lymphocytic leukemia Animals Antigen (tumor-associated) Antigens Automobiles Cancer Research Care and treatment CD19 antigen Cell Line Chimeric antigen receptors Critical Care Medicine Female Hematology Histocompatibility antigen HLA HLA-A Antigens - analysis Humans Immunotherapy Intensive Interleukin-12 - biosynthesis Internal Medicine Intracellular Leukemia Leukemia - therapy Lymphocytes Lymphocytes T Medicine Medicine & Public Health Mice Oncology original-article Ovarian cancer Ovarian Neoplasms - therapy Receptors, Antigen, T-Cell - immunology Recombinant Fusion Proteins - immunology Retroviridae - genetics T cell antigen receptors T cell receptors Therapy Transcriptome Tumors WT1 protein WT1 Proteins - analysis WT1 Proteins - immunology |
| title | Optimized T-cell receptor-mimic chimeric antigen receptor T cells directed toward the intracellular Wilms Tumor 1 antigen |
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