Safety and clinical efficacy of rapidly-generated trivirus-directed T cells as treatment for adenovirus, EBV, and CMV infections after allogeneic hematopoietic stem cell transplant

被引:176
作者
Gerdemann, Ulrike [1 ]
Katari, Usha L. [1 ]
Papadopoulou, Anastasia [1 ]
Keirnan, Jacqueline M. [1 ]
Craddock, John A. [1 ]
Liu, Hao [1 ]
Martinez, Caridad A. [1 ]
Kennedy-Nasser, Alana [1 ]
Leung, Kathryn S. [1 ]
Gottschalk, Stephen M. [1 ]
Krance, Robert A. [1 ]
Brenner, Malcolm K. [1 ]
Rooney, Cliona M. [1 ]
Heslop, Helen E. [1 ]
Leen, Ann M. [1 ]
机构
[1] Texas Childrens Hosp, Baylor Coll Med, Methodist Hosp, Ctr Cell & Gene Therapy, Houston, TX 77030 USA
关键词
EPSTEIN-BARR-VIRUS; POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISEASE; ADOPTIVE TRANSFER; VIRAL-INFECTIONS; LYMPHOCYTES; CYTOMEGALOVIRUS; PEPTIDE; IMMUNITY; THERAPY; HUMANS;
D O I
10.1038/mt.2013.151
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Adoptive transfer of virus-specific T cells can prevent and treat serious infections with Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (Adv) after allogeneic hematopoietic stem cell transplant. It has, however, proved difficult to make this approach widely available since infectious virus and viral vectors are required for T cell activation, followed by an intensive and prolonged culture period extending over several months. We now show that T cells targeting a range of viral antigens derived from EBV, CMV, and Adv can be reproducibly generated in a single culture over a 2-3-week period, using methods that exclude all viral components and employ a much-simplified culture technology. When administered to recipients of haploidentical (n = 5), matched unrelated (n = 3), mismatched unrelated (n = 1) or matched related (n = 1) transplants with active CMV (n = 3), Adv (n = 1), EBV (n = 2), EBV+Adv (n = 2) or CMV+Adv (n = 2) infections, the cells produced complete virological responses in 80%, including all patients with dual infections. In each case, a decrease in viral load correlated with an increase in the frequency of T cells directed against the infecting virus(es); both immediate and delayed toxicities were absent. This approach should increase both the feasibility and applicability of T cell therapy. The trial was registered at www.clinicaltrials.gov as NCT01070797.
引用
收藏
页码:2113 / 2121
页数:9
相关论文
共 42 条
[1]   Identification of a Coordinated CD8 and CD4 T Cell Response Directed Against Mismatched HLA Class I Causing Severe Acute Graft-versus-Host Disease [J].
Amir, Avital L. ;
Hagedoorn, Renate S. ;
van Luxemburg-Heijs, Simone A. P. ;
Marijt, Erik W. A. ;
Kruisselbrink, Alwine B. ;
Falkenburg, J. H. Frederik ;
Heemskerk, Mirjam H. M. .
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION, 2012, 18 (02) :210-219
[2]   Allo-HLA reactivity of virus-specific memory T cells is common [J].
Amir, Avital L. ;
D'Orsogna, Lloyd J. A. ;
Roelen, Dave L. ;
van Loenen, Marleen M. ;
Hagedoorn, Renate S. ;
de Boer, Renate ;
van der Hoorn, Menno A. W. G. ;
Kester, Michel G. D. ;
Doxiadis, Ilias I. N. ;
Falkenburg, J. H. Frederik ;
Claas, Frans H. J. ;
Heemskerk, Mirjam H. M. .
BLOOD, 2010, 115 (15) :3146-3157
[3]   Successful treatment of EBV-associated posttransplantation lymphoma after cord blood transplantation using third-party EBV-specific cytotoxic T lymphocytes [J].
Barker, Juliet N. ;
Doubrovina, Ekaterina ;
Sauter, Craig ;
Jaroscak, Jennifer J. ;
Perales, Miguel A. ;
Doubrovin, Mikhail ;
Prockop, Susan E. ;
Koehne, Guenther ;
O'Reilly, Richard J. .
BLOOD, 2010, 116 (23) :5045-5049
[4]   Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells [J].
Bunde, T ;
Kirchner, A ;
Hoffmeister, B ;
Habedank, D ;
Hetzer, R ;
Cherepnev, G ;
Proesch, S ;
Reinke, P ;
Volk, HD ;
Lehmkuhl, H ;
Kern, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 201 (07) :1031-1036
[5]   Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: Degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity [J].
Burrows, SR ;
Silins, SL ;
Khanna, R ;
Burrows, JM ;
Rischmueller, M ;
McCluskey, J ;
Moss, DJ .
EUROPEAN JOURNAL OF IMMUNOLOGY, 1997, 27 (07) :1726-1736
[6]   T-CELL RECEPTOR REPERTOIRE FOR A VIRAL EPITOPE IN HUMANS IS DIVERSIFIED BY TOLERANCE TO A BACKGROUND MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGEN [J].
BURROWS, SR ;
SILINS, SL ;
MOSS, DJ ;
KHANNA, R ;
MISKO, IS ;
ARGAET, VP .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 182 (06) :1703-1715
[7]   AN ALLORESPONSE IN HUMANS IS DOMINATED BY CYTOTOXIC T-LYMPHOCYTES (CTL) CROSS-REACTIVE WITH A SINGLE EPSTEIN-BARR-VIRUS CTL EPITOPE - IMPLICATIONS FOR GRAFT-VERSUS-HOST DISEASE [J].
BURROWS, SR ;
KHANNA, R ;
BURROWS, JM ;
MOSS, DJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1994, 179 (04) :1155-1161
[8]   Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers [J].
Cobbold, M ;
Khan, N ;
Pourgheysari, B ;
Tauro, S ;
McDonald, D ;
Osman, H ;
Assenmacher, M ;
Billingham, L ;
Steward, C ;
Crawley, C ;
Olavarria, E ;
Goldman, J ;
Chakraverty, R ;
Mahendra, P ;
Craddock, C ;
Moss, PAH .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (03) :379-386
[9]   New tools to monitor the impact of viral infection on the alloreactive T-cell repertoire [J].
D'Orsogna, L. J. ;
Amir, A. L. ;
Zoet, Y. M. ;
van der Meer-Prins, P. M. W. ;
van der Slik, A. R. ;
Kester, M. G. D. ;
Heemskerk, M. H. M. ;
Doxiadis, I. I. N. ;
Roelen, D. L. ;
Claas, F. H. J. .
TISSUE ANTIGENS, 2009, 74 (04) :290-297
[10]   Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation [J].
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. .
BLOOD, 2012, 119 (11) :2644-2656