Genetically modified donor leukocyte transfusion and graft-versus-leukemia effect after allogeneic stem cell transplantation

Hum Gene Ther. 2011 Jul;22(7):829-41. doi: 10.1089/hum.2010.162. Epub 2011 Mar 30.

Abstract

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34(+) cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Chimerism
  • Female
  • Fusion Proteins, bcr-abl / genetics
  • Genetic Vectors
  • Graft vs Host Disease / mortality
  • Graft vs Host Disease / prevention & control*
  • Graft vs Leukemia Effect*
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Immunosuppression Therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy*
  • Leukemia, Myeloid, Acute / therapy*
  • Leukocyte Transfusion*
  • Male
  • Middle Aged
  • Proteomics / methods
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Remission Induction
  • Retroviridae / genetics
  • Thymidine Kinase / genetics
  • Tissue Donors
  • Transduction, Genetic
  • Transgenes

Substances

  • Receptors, Antigen, T-Cell, alpha-beta
  • Thymidine Kinase
  • Fusion Proteins, bcr-abl