Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation

Kenneth P. Micklethwaite, Barbara Savoldo, Patrick J. Hanley, Ann M. Leen, Gail J. Demmler-Harrison, Laurence J.N. Cooper, Hao Liu, Adrian P. Gee, Elizabeth J. Shpall, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner, Catherine M. Bollard, Gianpietro Dotti

Research output: Contribution to journalArticle

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Abstract

Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR + CTLs produced interferon-γ (IFNγ) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 ± 104 to 1034 ± 304 spot-forming cells [SFCs]/10 5 T cells) and lysed primary B-ALL blasts in 51 Cr-release assays (mean, 66% ± 5%specific lysis; effector-target [E/T] ratio, 40:1) and the CD19 + Raji cell line (mean, 78% ± 17%) in contrast to nontransduced controls (8% ± 8% and 3% ± 2%). CB-derivedCAR + CTLs showed similar antiviral and antitumor function and both PB and CB CAR + CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.

Original languageEnglish (US)
Pages (from-to)2695-2703
Number of pages9
JournalBlood
Volume115
Issue number13
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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T-cells
Stem Cell Transplantation
Cytotoxic T-Lymphocytes
Stem cells
Fetal Blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cell culture
Antiviral Agents
Blood
B-Lymphocytes
Antigen Receptors
T-Lymphocytes
Recurrence
Infection
Viruses
Hematopoietic Stem Cells
Transplants
Adoptive Transfer
Hematopoietic Stem Cell Transplantation
Graft vs Host Disease

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. / Micklethwaite, Kenneth P.; Savoldo, Barbara; Hanley, Patrick J.; Leen, Ann M.; Demmler-Harrison, Gail J.; Cooper, Laurence J.N.; Liu, Hao; Gee, Adrian P.; Shpall, Elizabeth J.; Rooney, Cliona M.; Heslop, Helen E.; Brenner, Malcolm K.; Bollard, Catherine M.; Dotti, Gianpietro.

In: Blood, Vol. 115, No. 13, 01.04.2010, p. 2695-2703.

Research output: Contribution to journalArticle

Micklethwaite, KP, Savoldo, B, Hanley, PJ, Leen, AM, Demmler-Harrison, GJ, Cooper, LJN, Liu, H, Gee, AP, Shpall, EJ, Rooney, CM, Heslop, HE, Brenner, MK, Bollard, CM & Dotti, G 2010, 'Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation', Blood, vol. 115, no. 13, pp. 2695-2703. https://doi.org/10.1182/blood-2009-09-242263
Micklethwaite, Kenneth P. ; Savoldo, Barbara ; Hanley, Patrick J. ; Leen, Ann M. ; Demmler-Harrison, Gail J. ; Cooper, Laurence J.N. ; Liu, Hao ; Gee, Adrian P. ; Shpall, Elizabeth J. ; Rooney, Cliona M. ; Heslop, Helen E. ; Brenner, Malcolm K. ; Bollard, Catherine M. ; Dotti, Gianpietro. / Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation. In: Blood. 2010 ; Vol. 115, No. 13. pp. 2695-2703.
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abstract = "Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR + CTLs produced interferon-γ (IFNγ) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 ± 104 to 1034 ± 304 spot-forming cells [SFCs]/10 5 T cells) and lysed primary B-ALL blasts in 51 Cr-release assays (mean, 66{\%} ± 5{\%}specific lysis; effector-target [E/T] ratio, 40:1) and the CD19 + Raji cell line (mean, 78{\%} ± 17{\%}) in contrast to nontransduced controls (8{\%} ± 8{\%} and 3{\%} ± 2{\%}). CB-derivedCAR + CTLs showed similar antiviral and antitumor function and both PB and CB CAR + CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.",
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AU - Demmler-Harrison, Gail J.

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AU - Liu, Hao

AU - Gee, Adrian P.

AU - Shpall, Elizabeth J.

AU - Rooney, Cliona M.

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