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

85 Scopus citations

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]/105 T cells) and lysed primary B-ALL blasts in 51Cr-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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Micklethwaite, K. P., Savoldo, B., Hanley, P. J., Leen, A. M., Demmler-Harrison, G. J., Cooper, L. J. N., Liu, H., Gee, A. P., Shpall, E. J., Rooney, C. M., Heslop, H. E., Brenner, M. K., Bollard, C. M., & 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, 115(13), 2695-2703. https://doi.org/10.1182/blood-2009-09-242263