Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation
We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partia...
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| Veröffentlicht in: | Blood 2012-03, Vol.119 (11), p.2644-2656 |
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| creator | Doubrovina, Ekaterina Oflaz-Sozmen, Banu Prockop, Susan E. Kernan, Nancy A. Abramson, Sara Teruya-Feldstein, Julie Hedvat, Cyrus Chou, Joanne F. Heller, Glenn Barker, Juliet N. Boulad, Farid Castro-Malaspina, Hugo George, Diane Jakubowski, Ann Koehne, Guenther Papadopoulos, Esperanza B. Scaradavou, Andromachi Small, Trudy N. Khalaf, Ramzi Young, James W. O'Reilly, Richard J. |
| description | We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles. |
| doi_str_mv | 10.1182/blood-2011-08-371971 |
| format | Article |
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DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2011-08-371971</identifier><identifier>PMID: 22138512</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Biological and medical sciences ; Child ; Clinical Trials and Observations ; DNA, Viral - genetics ; Epstein-Barr Virus Infections - etiology ; Epstein-Barr Virus Infections - therapy ; Female ; Hematologic and hematopoietic diseases ; Hematopoietic Stem Cell Transplantation - adverse effects ; Herpesvirus 4, Human - pathogenicity ; Humans ; Immunotherapy, Adoptive ; Infectious diseases ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphoma - etiology ; Lymphoma - therapy ; Lymphoproliferative Disorders - etiology ; Lymphoproliferative Disorders - therapy ; Male ; Medical sciences ; Middle Aged ; Polymerase Chain Reaction ; T-Lymphocytes - immunology ; T-Lymphocytes, Cytotoxic - immunology ; T-Lymphocytes, Cytotoxic - transplantation ; Transplantation ; Transplantation, Homologous ; Viral diseases ; Young Adult</subject><ispartof>Blood, 2012-03, Vol.119 (11), p.2644-2656</ispartof><rights>2012 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><rights>2012 by The American Society of Hematology 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c492t-5304486dd24aef796d9fe1ec5aa02caf2028fc3dbb82126d5bfe67a859f4924d3</citedby><cites>FETCH-LOGICAL-c492t-5304486dd24aef796d9fe1ec5aa02caf2028fc3dbb82126d5bfe67a859f4924d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25630134$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22138512$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Doubrovina, Ekaterina</creatorcontrib><creatorcontrib>Oflaz-Sozmen, Banu</creatorcontrib><creatorcontrib>Prockop, Susan E.</creatorcontrib><creatorcontrib>Kernan, Nancy A.</creatorcontrib><creatorcontrib>Abramson, Sara</creatorcontrib><creatorcontrib>Teruya-Feldstein, Julie</creatorcontrib><creatorcontrib>Hedvat, Cyrus</creatorcontrib><creatorcontrib>Chou, Joanne F.</creatorcontrib><creatorcontrib>Heller, Glenn</creatorcontrib><creatorcontrib>Barker, Juliet N.</creatorcontrib><creatorcontrib>Boulad, Farid</creatorcontrib><creatorcontrib>Castro-Malaspina, Hugo</creatorcontrib><creatorcontrib>George, Diane</creatorcontrib><creatorcontrib>Jakubowski, Ann</creatorcontrib><creatorcontrib>Koehne, Guenther</creatorcontrib><creatorcontrib>Papadopoulos, Esperanza B.</creatorcontrib><creatorcontrib>Scaradavou, Andromachi</creatorcontrib><creatorcontrib>Small, Trudy N.</creatorcontrib><creatorcontrib>Khalaf, Ramzi</creatorcontrib><creatorcontrib>Young, James W.</creatorcontrib><creatorcontrib>O'Reilly, Richard J.</creatorcontrib><title>Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation</title><title>Blood</title><addtitle>Blood</addtitle><description>We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Clinical Trials and Observations</subject><subject>DNA, Viral - genetics</subject><subject>Epstein-Barr Virus Infections - etiology</subject><subject>Epstein-Barr Virus Infections - therapy</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematopoietic Stem Cell Transplantation - adverse effects</subject><subject>Herpesvirus 4, Human - pathogenicity</subject><subject>Humans</subject><subject>Immunotherapy, Adoptive</subject><subject>Infectious diseases</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphoma - etiology</subject><subject>Lymphoma - therapy</subject><subject>Lymphoproliferative Disorders - etiology</subject><subject>Lymphoproliferative Disorders - therapy</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Polymerase Chain Reaction</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>T-Lymphocytes, Cytotoxic - transplantation</subject><subject>Transplantation</subject><subject>Transplantation, Homologous</subject><subject>Viral diseases</subject><subject>Young Adult</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1vFSEUhidGY2-r_8AYNsZFMwrMF7MxqU39SJq4qW4JA4cOhgEE7m3u7_APy3ivrW5cETjv-3LOearqBcFvCGH07WS9VzXFhNSY1c1AxoE8qjako6zGmOLH1QZj3NdteT-pTlP6jjFpG9o9rU4oJQ3rCN1UPy-UD9nsAJll2TqfZ4gi7NGdyTPaugQWZAaFfERX77_VKYA02kh0gyRYm5Auhcn4kPZ1iH4HbpWdI7tfwuwXkZDQGSIS1vpbcFCcMywi--AN5HJbU1COwqVghcsiG--eVU-0sAmeH8-z6uuHq5vLT_X1l4-fLy-ua9mONNddg9uW9UrRVoAexl6NGgjITghMpdAUU6Zlo6aJUUJ71U0a-kGwbtTF36rmrHp3yA3baQElwZVGLA_RLCLuuReG_1txZua3fsebhhA6sBLw-hgQ_Y8tpMwXk9aJhAO_TXykbMT90OKibA9KGX1KEfT9LwTzFSf_jZOvODlm_ICz2F7-3eG96Q-_Inh1FIgkhdVlkdKkB13XN5g07cOoUPa5MxB5kgacBGViAcyVN__v5BfgKMOb</recordid><startdate>20120315</startdate><enddate>20120315</enddate><creator>Doubrovina, Ekaterina</creator><creator>Oflaz-Sozmen, Banu</creator><creator>Prockop, Susan E.</creator><creator>Kernan, Nancy A.</creator><creator>Abramson, Sara</creator><creator>Teruya-Feldstein, Julie</creator><creator>Hedvat, Cyrus</creator><creator>Chou, Joanne F.</creator><creator>Heller, Glenn</creator><creator>Barker, Juliet N.</creator><creator>Boulad, Farid</creator><creator>Castro-Malaspina, Hugo</creator><creator>George, Diane</creator><creator>Jakubowski, Ann</creator><creator>Koehne, Guenther</creator><creator>Papadopoulos, Esperanza B.</creator><creator>Scaradavou, Andromachi</creator><creator>Small, Trudy N.</creator><creator>Khalaf, Ramzi</creator><creator>Young, James W.</creator><creator>O'Reilly, Richard J.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><general>American Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20120315</creationdate><title>Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation</title><author>Doubrovina, Ekaterina ; Oflaz-Sozmen, Banu ; Prockop, Susan E. ; Kernan, Nancy A. ; Abramson, Sara ; Teruya-Feldstein, Julie ; Hedvat, Cyrus ; Chou, Joanne F. ; Heller, Glenn ; Barker, Juliet N. ; Boulad, Farid ; Castro-Malaspina, Hugo ; George, Diane ; Jakubowski, Ann ; Koehne, Guenther ; Papadopoulos, Esperanza B. ; Scaradavou, Andromachi ; Small, Trudy N. ; Khalaf, Ramzi ; Young, James W. ; O'Reilly, Richard J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c492t-5304486dd24aef796d9fe1ec5aa02caf2028fc3dbb82126d5bfe67a859f4924d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Clinical Trials and Observations</topic><topic>DNA, Viral - genetics</topic><topic>Epstein-Barr Virus Infections - etiology</topic><topic>Epstein-Barr Virus Infections - therapy</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hematopoietic Stem Cell Transplantation - adverse effects</topic><topic>Herpesvirus 4, Human - pathogenicity</topic><topic>Humans</topic><topic>Immunotherapy, Adoptive</topic><topic>Infectious diseases</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. 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DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>22138512</pmid><doi>10.1182/blood-2011-08-371971</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Blood, 2012-03, Vol.119 (11), p.2644-2656 |
| issn | 0006-4971 1528-0020 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Biological and medical sciences Child Clinical Trials and Observations DNA, Viral - genetics Epstein-Barr Virus Infections - etiology Epstein-Barr Virus Infections - therapy Female Hematologic and hematopoietic diseases Hematopoietic Stem Cell Transplantation - adverse effects Herpesvirus 4, Human - pathogenicity Humans Immunotherapy, Adoptive Infectious diseases Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma - etiology Lymphoma - therapy Lymphoproliferative Disorders - etiology Lymphoproliferative Disorders - therapy Male Medical sciences Middle Aged Polymerase Chain Reaction T-Lymphocytes - immunology T-Lymphocytes, Cytotoxic - immunology T-Lymphocytes, Cytotoxic - transplantation Transplantation Transplantation, Homologous Viral diseases Young Adult |
| title | Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation |
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