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

Ulrike Gerdemann, Usha L. Katari, Anastasia Papadopoulou, Jacqueline M. Keirnan, John A. Craddock, Hao Liu, Caridad A. Martinez, Alana Kennedy-Nasser, Kathryn S. Leung, Stephen M. Gottschalk, Robert A. Krance, Malcolm K. Brenner, Cliona M. Rooney, Helen E. Heslop, Ann M. Leen

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2113-2121
Number of pages9
JournalMolecular Therapy
Volume21
Issue number11
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

Fingerprint

Epstein-Barr Virus Infections
Cytomegalovirus Infections
Hematopoietic Stem Cells
Adenoviridae
Cytomegalovirus
T-Lymphocytes
Transplants
Safety
Human Herpesvirus 4
Viruses
Therapeutics
Viral Structures
Adoptive Transfer
Viral Antigens
Cell- and Tissue-Based Therapy
Infection
Viral Load
Technology

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

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. / 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.

In: Molecular Therapy, Vol. 21, No. 11, 01.01.2013, p. 2113-2121.

Research output: Contribution to journalArticle

Gerdemann, U, Katari, UL, Papadopoulou, A, Keirnan, JM, Craddock, JA, Liu, H, Martinez, CA, Kennedy-Nasser, A, Leung, KS, Gottschalk, SM, Krance, RA, Brenner, MK, Rooney, CM, Heslop, HE & Leen, AM 2013, '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', Molecular Therapy, vol. 21, no. 11, pp. 2113-2121. https://doi.org/10.1038/mt.2013.151
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. / 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. In: Molecular Therapy. 2013 ; Vol. 21, No. 11. pp. 2113-2121.
@article{4a0b5df242fd498bb47d6dafadac9e09,
title = "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",
abstract = "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.",
author = "Ulrike Gerdemann and Katari, {Usha L.} and Anastasia Papadopoulou and Keirnan, {Jacqueline M.} and Craddock, {John A.} and Hao Liu and Martinez, {Caridad A.} and Alana Kennedy-Nasser and Leung, {Kathryn S.} and Gottschalk, {Stephen M.} and Krance, {Robert A.} and Brenner, {Malcolm K.} and Rooney, {Cliona M.} and Heslop, {Helen E.} and Leen, {Ann M.}",
year = "2013",
month = "1",
day = "1",
doi = "10.1038/mt.2013.151",
language = "English (US)",
volume = "21",
pages = "2113--2121",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - 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

AU - Gerdemann, Ulrike

AU - Katari, Usha L.

AU - Papadopoulou, Anastasia

AU - Keirnan, Jacqueline M.

AU - Craddock, John A.

AU - Liu, Hao

AU - Martinez, Caridad A.

AU - Kennedy-Nasser, Alana

AU - Leung, Kathryn S.

AU - Gottschalk, Stephen M.

AU - Krance, Robert A.

AU - Brenner, Malcolm K.

AU - Rooney, Cliona M.

AU - Heslop, Helen E.

AU - Leen, Ann M.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84887501471&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887501471&partnerID=8YFLogxK

U2 - 10.1038/mt.2013.151

DO - 10.1038/mt.2013.151

M3 - Article

C2 - 23783429

AN - SCOPUS:84887501471

VL - 21

SP - 2113

EP - 2121

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 11

ER -