First-in-Man Clinical Results With Good Manufacturing Practice (GMP)-compliant Polypeptide-expanded Adenovirus-specific T Cells After Haploidentical Hematopoietic Stem Cell Transplantation

被引：41

作者：

Geyeregger, Rene ^{[1
,2
]}

Freimueller, Christine ^{[1
,2
]}

Stemberger, Julia ^{[1
]}

Artwohl, Michaela ^{[3
]}

Witt, Volker ^{[5
]}

Lion, Thomas ^{[4
,7
]}

Fischer, Gottfried ^{[8
]}

Lawitschka, Anita ^{[6
,7
]}

Ritter, Julia ^{[9
]}

Hummel, Michael ^{[9
]}

Holter, Wolfgang ^{[6
,7
]}

Fritsch, Gerhard ^{[1
,7
]}

Matthes-Martin, Susanne ^{[6
,7
]}

机构：

[1] CCRI, Dept Clin Cell Biol, A-1090 Vienna, Austria

[2] CCRI, FACS Core Unit, A-1090 Vienna, Austria

[3] CCRI, Dept Qual Management, A-1090 Vienna, Austria

[4] CCRI, Dept Mol Microbiol, A-1090 Vienna, Austria

[5] St Anna Childrens Hosp, A-1090 Vienna, Austria

[6] St Anna Childrens Hosp, Dept Stem Cell Transplantat, A-1090 Vienna, Austria

[7] Med Univ Vienna, Dept Pediat, Vienna, Austria

[8] Med Univ Vienna, Dept Blood Grp Serol & Transfus Med, Vienna, Austria

[9] Charite, Inst Pathol, D-13353 Berlin, Germany

来源：

JOURNAL OF IMMUNOTHERAPY | 2014年 / 37卷 / 04期

关键词：

hematopoietic stem cell transplantation; adenovirus-specific T cells; adoptive immunotherapy; virus-specific polypeptides; good manufacturing practice; ADOPTIVE TRANSFER; LYMPHOCYTES; INFECTIONS; THERAPY;

D O I：

10.1097/CJI.0000000000000034

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Adoptive immunotherapy against viral infections is a promising treatment option for patients after hematopoietic stem cell transplantation. However, the generation of virus-specific T cells is either cost-intensive or time-consuming. We developed the first GMP-compliant protocol to generate donor-derived adenovirus (HAdV), cytomegalovirus, and Epstein-Barr virus-specific T-cell lines (TCLs) within 12 days by the use of overlapping polypeptides derived from different viruses in combination with IL-15. Two patients after undergoing haploidentical hematopoietic stem cell transplantation with HAdV viremia displaying rising viral loads despite treatment with cidofovir received 1x10(4) donor-derived short-term expanded HAdV-specific TCLs per kg body weight. In both patients, HAdV-specific T cells could be detected by IFN--ELISpot 30 and 22 days postinfusion, and resulted in complete clearance or >1.5 log reduction of viral load within 15 and 18 days, respectively. This protocol facilitates rapid and cost-effective generation of virus-specific TCLs, which appear to provide an effective treatment option.

引用

页码：245 / 249

页数：5

共 15 条

[1] Adoptive Immunotherapy With CMV-specific Cytotoxic T Lymphocytes for Stem Cell Transplant Patients With Refractory CMV Infections [J].

Bao, Lei ;

Cowan, Morton J. ;

Dunham, Kimberly ;

Horn, Biljana ;

McGuirk, Joseph ;

Gilman, Andrew ;

Lucas, Kenneth G. .

JOURNAL OF IMMUNOTHERAPY, 2012, 35 (03) :293-298

[2] Impaired Functionality of Antiviral T Cells in G-CSF Mobilized Stem Cell Donors: Implications for the Selection of CTL Donor [J].

Bunse, Carola E. ;

Borchers, Sylvia ;

Varanasi, Pavankumar R. ;

Tischer, Sabine ;

Figueiredo, Constanca ;

Immenschuh, Stephan ;

Kalinke, Ulrich ;

Koehl, Ulrike ;

Goudeva, Lilia ;

Maecker-Kolhoff, Britta ;

Ganser, Arnold ;

Blasczyk, Rainer ;

Weissinger, Eva M. ;

Eiz-Vesper, Britta .

PLOS ONE, 2013, 8 (12)

[3] Adoptive Immunotherapy With Antigen-Specific T Cells During Extracorporeal Membrane Oxygenation (ECMO) for Adenovirus-Related Respiratory Failure in a Child Given Haploidentical Stem Cell Transplantation [J].

Di Nardo, Matteo ;

Li Pira, Giuseppina ;

Amodeo, Antonio ;

Cecchetti, Corrado ;

Giorda, Ezio ;

Ceccarelli, Stefano ;

Brescia, Letizia P. ;

Pirozzi, Nicola ;

Rutella, Sergio ;

Locatelli, Franco ;

Bertaina, Alice .

PEDIATRIC BLOOD & CANCER, 2014, 61 (02) :376-379

[4] Safe adoptive transfer of virus-specific T-cell immunity for the treatment of systemic adenovirus infection after allogeneic stem cell transplantation [J].

Feuchtinger, T ;

Matthes-Martin, S ;

Richard, C ;

Lion, T ;

Fuhrer, M ;

Hamprecht, K ;

Handgretinger, R ;

Peters, C ;

Schuster, FR ;

Beck, R ;

Schumm, M ;

Lotfi, R ;

Jahn, G ;

Lang, P .

BRITISH JOURNAL OF HAEMATOLOGY, 2006, 134 (01) :64-76

[5] Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation [J].

Feuchtinger, Tobias ;

Opherk, Kathrin ;

Bethge, Wolfgang A. ;

Topp, Max S. ;

Schuster, Friedhelm R. ;

Weissinger, Eva M. ;

Mohty, Mohamad ;

Or, Reuven ;

Maschan, Michael ;

Schumm, Michael ;

Hamprecht, Klaus ;

Handgretinger, Rupert ;

Lang, Peter ;

Einsele, Hermann .

BLOOD, 2010, 116 (20) :4360-4367

[6] 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 [J].

Gerdemann, Ulrike ;

Katari, Usha L. ;

Papadopoulou, Anastasia ;

Keirnan, Jacqueline M. ;

Craddock, John A. ;

Liu, Hao ;

Martinez, Caridad A. ;

Kennedy-Nasser, Alana ;

Leung, Kathryn S. ;

Gottschalk, Stephen M. ;

Krance, Robert A. ;

Brenner, Malcolm K. ;

Rooney, Cliona M. ;

Heslop, Helen E. ;

Leen, Ann M. .

MOLECULAR THERAPY, 2013, 21 (11) :2113-2121

[7] Rapidly Generated Multivirus-specific Cytotoxic T Lymphocytes for the Prophylaxis and Treatment of Viral Infections [J].

Gerdemann, Ulrike ;

Keirnan, Jacqueline M. ;

Katari, Usha L. ;

Yanagisawa, Ryu ;

Christin, Anne S. ;

Huye, Leslie E. ;

Perna, Serena K. ;

Ennamuri, Sravya ;

Gottschalk, Stephen ;

Brenner, Malcolm K. ;

Heslop, Helen E. ;

Rooney, Cliona M. ;

Leen, Ann M. .

MOLECULAR THERAPY, 2012, 20 (08) :1622-1632

[8] Short-Term In-Vitro Expansion Improves Monitoring and Allows Affordable Generation of Virus-Specific T-Cells against Several Viruses for a Broad Clinical Application [J].

Geyeregger, Rene ;

Freimueller, Christine ;

Stevanovic, Stefan ;

Stemberger, Julia ;

Mester, Gabor ;

Dmytrus, Jasmin ;

Lion, Thomas ;

Rammensee, Hans-Georg ;

Fischer, Gottfried ;

Eiz-Vesper, Britta ;

Lawitschka, Anita ;

Matthes, Susanne ;

Fritsch, Gerhard .

PLOS ONE, 2013, 8 (04)

[9] Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients [J].

Hiwarkar, P. ;

Gaspar, H. B. ;

Gilmour, K. ;

Jagani, M. ;

Chiesa, R. ;

Bennett-Rees, N. ;

Breuer, J. ;

Rao, K. ;

Cale, C. ;

Goulden, N. ;

Davies, G. ;

Amrolia, P. ;

Veys, P. ;

Qasim, W. .

BONE MARROW TRANSPLANTATION, 2013, 48 (06) :803-808

[10] Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation [J].

Leen, Ann M. ;

Bollard, Catherine M. ;

Mendizabal, Adam M. ;

Shpall, Elizabeth J. ;

Szabolcs, Paul ;

Antin, Joseph H. ;

Kapoor, Neena ;

Pai, Sung-Yun ;

Rowley, Scott D. ;

Kebriaei, Partow ;

Dey, Bimalangshu R. ;

Grilley, Bambi J. ;

Gee, Adrian P. ;

Brenner, Malcolm K. ;

Rooney, Cliona M. ;

Heslop, Helen E. .

BLOOD, 2013, 121 (26) :5113-5123

← 1 2 →