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

  1. Kenneth P. Micklethwaite1,
  2. Barbara Savoldo2,
  3. Patrick J. Hanley3,
  4. Ann M. Leen1,
  5. Gail J. Demmler-Harrison4,
  6. Laurence J.N. Cooper5,
  7. Hao Liu6,
  8. Adrian P. Gee1,
  9. Elizabeth J. Shpall5,
  10. Cliona M. Rooney1,
  11. Helen E. Heslop1,
  12. Malcolm K. Brenner1,
  13. Catherine M. Bollard1, and
  14. Gianpietro Dotti1,*
  1. 1 Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and The Methodist Hospital, Houston, Texas;
  2. 2 Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital and The Methodist Hospital, Houston, Texas;
  3. 3 Department of Immunology, Baylor College of Medicine, Texas Children's Hospital and The Methodist Hospital, Houston, Texas;
  4. 4 Department of Pathology, Baylor College of Medicine, Texas Children's Hospital and The Methodist Hospital, Houston, Texas;
  5. 5 Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas;
  6. 6 Department of Medicine, Baylor College of Medicine, Texas Children's Hospital and The Methodist Hospital, Houston, Texas
  1. * Corresponding author; email: gdotti{at}bcm.tmc.edu

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 transplants 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 IFNγ in response to cytomegalovirus-pp65, adenovirus-hexon and Epstein-Barr virus pepmixes (from, 205±104 to 1034±304 SFC/105 T-cells) and lysed primary B-ALL blasts in Cr release assays (mean 66%±5% specific lysis, E:T ratio 40:1) and the CD19+ Raji cell line (mean 78%±17%) in contrast to non-transduced controls (8%±8% and 3%±2%). CB-derived CAR+ CTLs showed similar antiviral and antitumor function and both PB and CB CAR+ CTL completely eliminated B-ALL blasts over 5 days 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.

  • Submitted September 9, 2009.
  • Accepted January 8, 2010.

This Article

  1. Published online before print January 28, 2010, doi: 10.1182/blood-2009-09-242263 Blood January 28, 2010 blood-2009-09-242263
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