Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation

Patrick J. Hanley, Donald R. Shaffer, Conrad R.Y. Cruz, Stephanie Ku, Benjamin Tzou, Hao Liu, Gail Demmler-Harrison, Helen E. Heslop, Clio M. Rooney, Stephen Gottschalk, Catherine M. Bollard

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background aims. Hematopoietic stem cell transplant (HSCT) is the treatment of choice for a proportion of patients with hematologic malignancies as well as for non-malignant diseases. However, viral infections, particularly EpsteinBarr virus (EBV), cytomegalovirus (CMV) and adenovirus (Ad), remain problematic after transplant despite the use of antiviral drugs. We have shown that cytotoxic T lymphocytes (CTL) generated against CMV-pp65, EBV and Ad antigens in a single culture are capable of controlling infections with all three viruses after HSCT. Although pp65-specific CTL have proved efficacious for the control of CMV infection, several reports highlight the importance of targeting additional CMV antigens. Methods. To expand multivirus-specific T cells with activity against both CMV-pp65 and CMV-IE-1, peripheral blood mononuclear cells (PBMC) were transduced with the adenoviral vector (Ad5f35-IE-1-I-pp65). After 9-12 days the CTL were restimulated with autologous EBV-transformed B cells transduced with the same Ad vector. Results. After 18 days in culture nine CTL lines expanded from less than 1.5 × 10 7 PBMC to a mean of 6.1 × 10 7 T cells that recognized CMV antigens pp65 [median 273 spot-forming cells (SFC), range 47-995] and IE-1 (median 154 SFC, range 11-505), the Ad antigens hexon (median 153 SFC, range 26-465) and penton (median 37 SFC, range 1-353), as well as EBV lymphoblastoid cell lines (median 55 SFC, range 9-301). Importantly, the T cells recognized at least two antigens per virus and lysed virus peptide-pulsed targets. Conclusions. CTL that target at least two antigens each of CMV, EBV and Ad should have clinical benefit with broad coverage of all three viruses and enhanced control of CMV infections compared with current protocols.

Original languageEnglish (US)
Pages (from-to)976-986
Number of pages11
JournalCytotherapy
Volume13
Issue number8
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

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Stem Cell Transplantation
Cytomegalovirus
Human Herpesvirus 4
Adenoviridae
Antiviral Agents
Viruses
T-Lymphocytes
Antigens
Cytotoxic T-Lymphocytes
Cytomegalovirus Infections
Hematopoietic Stem Cells
Transplants
Blood Cells
Virus Diseases
Hematologic Neoplasms
B-Lymphocytes
Cell Line
Peptides
Infection

Keywords

  • adenovirus
  • adoptive immunotherapy
  • antiviral immunity
  • cytomegalovirus
  • cytotoxic T lymphocytes
  • EpsteinBarr virus
  • stem cell transplant

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Transplantation
  • Cancer Research

Cite this

Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation. / Hanley, Patrick J.; Shaffer, Donald R.; Cruz, Conrad R.Y.; Ku, Stephanie; Tzou, Benjamin; Liu, Hao; Demmler-Harrison, Gail; Heslop, Helen E.; Rooney, Clio M.; Gottschalk, Stephen; Bollard, Catherine M.

In: Cytotherapy, Vol. 13, No. 8, 01.01.2011, p. 976-986.

Research output: Contribution to journalArticle

Hanley, PJ, Shaffer, DR, Cruz, CRY, Ku, S, Tzou, B, Liu, H, Demmler-Harrison, G, Heslop, HE, Rooney, CM, Gottschalk, S & Bollard, CM 2011, 'Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation', Cytotherapy, vol. 13, no. 8, pp. 976-986. https://doi.org/10.3109/14653249.2011.575356
Hanley, Patrick J. ; Shaffer, Donald R. ; Cruz, Conrad R.Y. ; Ku, Stephanie ; Tzou, Benjamin ; Liu, Hao ; Demmler-Harrison, Gail ; Heslop, Helen E. ; Rooney, Clio M. ; Gottschalk, Stephen ; Bollard, Catherine M. / Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation. In: Cytotherapy. 2011 ; Vol. 13, No. 8. pp. 976-986.
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abstract = "Background aims. Hematopoietic stem cell transplant (HSCT) is the treatment of choice for a proportion of patients with hematologic malignancies as well as for non-malignant diseases. However, viral infections, particularly EpsteinBarr virus (EBV), cytomegalovirus (CMV) and adenovirus (Ad), remain problematic after transplant despite the use of antiviral drugs. We have shown that cytotoxic T lymphocytes (CTL) generated against CMV-pp65, EBV and Ad antigens in a single culture are capable of controlling infections with all three viruses after HSCT. Although pp65-specific CTL have proved efficacious for the control of CMV infection, several reports highlight the importance of targeting additional CMV antigens. Methods. To expand multivirus-specific T cells with activity against both CMV-pp65 and CMV-IE-1, peripheral blood mononuclear cells (PBMC) were transduced with the adenoviral vector (Ad5f35-IE-1-I-pp65). After 9-12 days the CTL were restimulated with autologous EBV-transformed B cells transduced with the same Ad vector. Results. After 18 days in culture nine CTL lines expanded from less than 1.5 × 10 7 PBMC to a mean of 6.1 × 10 7 T cells that recognized CMV antigens pp65 [median 273 spot-forming cells (SFC), range 47-995] and IE-1 (median 154 SFC, range 11-505), the Ad antigens hexon (median 153 SFC, range 26-465) and penton (median 37 SFC, range 1-353), as well as EBV lymphoblastoid cell lines (median 55 SFC, range 9-301). Importantly, the T cells recognized at least two antigens per virus and lysed virus peptide-pulsed targets. Conclusions. CTL that target at least two antigens each of CMV, EBV and Ad should have clinical benefit with broad coverage of all three viruses and enhanced control of CMV infections compared with current protocols.",
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T1 - Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation

AU - Hanley, Patrick J.

AU - Shaffer, Donald R.

AU - Cruz, Conrad R.Y.

AU - Ku, Stephanie

AU - Tzou, Benjamin

AU - Liu, Hao

AU - Demmler-Harrison, Gail

AU - Heslop, Helen E.

AU - Rooney, Clio M.

AU - Gottschalk, Stephen

AU - Bollard, Catherine M.

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N2 - Background aims. Hematopoietic stem cell transplant (HSCT) is the treatment of choice for a proportion of patients with hematologic malignancies as well as for non-malignant diseases. However, viral infections, particularly EpsteinBarr virus (EBV), cytomegalovirus (CMV) and adenovirus (Ad), remain problematic after transplant despite the use of antiviral drugs. We have shown that cytotoxic T lymphocytes (CTL) generated against CMV-pp65, EBV and Ad antigens in a single culture are capable of controlling infections with all three viruses after HSCT. Although pp65-specific CTL have proved efficacious for the control of CMV infection, several reports highlight the importance of targeting additional CMV antigens. Methods. To expand multivirus-specific T cells with activity against both CMV-pp65 and CMV-IE-1, peripheral blood mononuclear cells (PBMC) were transduced with the adenoviral vector (Ad5f35-IE-1-I-pp65). After 9-12 days the CTL were restimulated with autologous EBV-transformed B cells transduced with the same Ad vector. Results. After 18 days in culture nine CTL lines expanded from less than 1.5 × 10 7 PBMC to a mean of 6.1 × 10 7 T cells that recognized CMV antigens pp65 [median 273 spot-forming cells (SFC), range 47-995] and IE-1 (median 154 SFC, range 11-505), the Ad antigens hexon (median 153 SFC, range 26-465) and penton (median 37 SFC, range 1-353), as well as EBV lymphoblastoid cell lines (median 55 SFC, range 9-301). Importantly, the T cells recognized at least two antigens per virus and lysed virus peptide-pulsed targets. Conclusions. CTL that target at least two antigens each of CMV, EBV and Ad should have clinical benefit with broad coverage of all three viruses and enhanced control of CMV infections compared with current protocols.

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KW - adoptive immunotherapy

KW - antiviral immunity

KW - cytomegalovirus

KW - cytotoxic T lymphocytes

KW - EpsteinBarr virus

KW - stem cell transplant

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