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

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.

• Authors: Sylvia Borchers, Elena Provasi, Anna Silvani, Marina Radrizzani, Claudia Benati, Elke Dammann, Annika Krons, Julia Kontsendorn, Joerg Schmidtke, Wolfgang Kuehnau, Nils von Neuhoff, Michael Stadler, Fabio Ciceri, Chiara Bonini, Arnold Ganser, Bernd Hertenstein, Eva M Weissinger
• Journal: Human gene therapy (Hum Gene Ther) Vol. 22 Issue 7 Pg. 829-41 (Jul 2011) ISSN: 1557-7422 [Electronic] United States
• PMID: 21091264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Chimerism
• Female
• Fusion Proteins, bcr-abl (genetics)
• Genetic Vectors
• Graft vs Host Disease (mortality, 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