Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation

Ifigeneia Tzannou, Anastasia Papadopoulou, Swati Naik, Kathryn Leung, Caridad A. Martinez, Carlos A. Ramos, George Carrum, Ghadir Sasa, Premal Lulla, Ayumi Watanabe, Manik Kuvalekar, Adrian P. Gee, Meng Fen Wu, Hao Liu, Bambi J. Grilley, Robert A. Krance, Stephen Gottschalk, Malcolm K. Brenner, Cliona M. Rooney, Helen E. Heslop & 2 others Ann M. Leen, Bilal Omer

Research output: Contribution to journalArticle

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Abstract

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available offthe-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

Original languageEnglish (US)
Pages (from-to)3547-3557
Number of pages11
JournalJournal of Clinical Oncology
Volume35
Issue number31
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

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BK Virus
Human Herpesvirus 6
Adenoviridae Infections
Epstein-Barr Virus Infections
Hematopoietic Stem Cell Transplantation
Cytomegalovirus
Viruses
T-Lymphocytes
Infection
Virus Diseases
Human Herpesvirus 4
Adenoviridae
Antiviral Agents
Phase II Clinical Trials
Cystitis
Graft vs Host Disease
Hematuria
Epitopes
Tissue Donors
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. / Tzannou, Ifigeneia; Papadopoulou, Anastasia; Naik, Swati; Leung, Kathryn; Martinez, Caridad A.; Ramos, Carlos A.; Carrum, George; Sasa, Ghadir; Lulla, Premal; Watanabe, Ayumi; Kuvalekar, Manik; Gee, Adrian P.; Wu, Meng Fen; Liu, Hao; Grilley, Bambi J.; Krance, Robert A.; Gottschalk, Stephen; Brenner, Malcolm K.; Rooney, Cliona M.; Heslop, Helen E.; Leen, Ann M.; Omer, Bilal.

In: Journal of Clinical Oncology, Vol. 35, No. 31, 01.11.2017, p. 3547-3557.

Research output: Contribution to journalArticle

Tzannou, I, Papadopoulou, A, Naik, S, Leung, K, Martinez, CA, Ramos, CA, Carrum, G, Sasa, G, Lulla, P, Watanabe, A, Kuvalekar, M, Gee, AP, Wu, MF, Liu, H, Grilley, BJ, Krance, RA, Gottschalk, S, Brenner, MK, Rooney, CM, Heslop, HE, Leen, AM & Omer, B 2017, 'Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation', Journal of Clinical Oncology, vol. 35, no. 31, pp. 3547-3557. https://doi.org/10.1200/JCO.2017.73.0655
Tzannou, Ifigeneia ; Papadopoulou, Anastasia ; Naik, Swati ; Leung, Kathryn ; Martinez, Caridad A. ; Ramos, Carlos A. ; Carrum, George ; Sasa, Ghadir ; Lulla, Premal ; Watanabe, Ayumi ; Kuvalekar, Manik ; Gee, Adrian P. ; Wu, Meng Fen ; Liu, Hao ; Grilley, Bambi J. ; Krance, Robert A. ; Gottschalk, Stephen ; Brenner, Malcolm K. ; Rooney, Cliona M. ; Heslop, Helen E. ; Leen, Ann M. ; Omer, Bilal. / Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 31. pp. 3547-3557.
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abstract = "Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available offthe-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92{\%} (95{\%} CI, 78.1{\%} to 98.3{\%}) overall and the following rates by virus: 100{\%} for BKV (n = 16), 94{\%} for CMV (n = 17), 71{\%} for AdV (n = 7), 100{\%} for EBV (n = 2), and 67{\%} for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.",
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T1 - Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation

AU - Tzannou, Ifigeneia

AU - Papadopoulou, Anastasia

AU - Naik, Swati

AU - Leung, Kathryn

AU - Martinez, Caridad A.

AU - Ramos, Carlos A.

AU - Carrum, George

AU - Sasa, Ghadir

AU - Lulla, Premal

AU - Watanabe, Ayumi

AU - Kuvalekar, Manik

AU - Gee, Adrian P.

AU - Wu, Meng Fen

AU - Liu, Hao

AU - Grilley, Bambi J.

AU - Krance, Robert A.

AU - Gottschalk, Stephen

AU - Brenner, Malcolm K.

AU - Rooney, Cliona M.

AU - Heslop, Helen E.

AU - Leen, Ann M.

AU - Omer, Bilal

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available offthe-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

AB - Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available offthe-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

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