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 þ 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 replicationdeficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (DLNGFR) 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.

Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation

“…Most notably, lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene (TK-cells) are widely applicable to a variety of hematologic malignancies [9][10][11][12][13][14][15][16]. TK-cells can be promptly eliminated by ganciclovir administration, which allows GVHD to be safely managed.…”

Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world

“…In the TK suicide gene/ prodrug system, only alloreactive gene-modified T cells that proliferate actively during GVHD are killed by GCV, whereas resting transduced T cells and untransduced cells are spared. TK gene therapy has proven to be safe, with no documented adverse events related to the gene-transfer procedure, including appearance of replication-competent retroviruses or genotoxic effects of vector integration [61][62][63][64][65][66][67][68][69][70][71].…”

Synergistic effect of chimeric antigen receptors and cytokineinduced killer cells: An innovative combination for cancer therapy

“…For complete control and timely intervention in the event undesired reactions occur, transduced cells should be introduced with inducible suicide genes (Ramos and Dotti, 2011). This approach includes the thymidine kinase gene of Herpes Simplex Virus (HSV-TK) (Borchers et al, 2011), Casp9 suicide system (Ciceri et al, 2009;Di Stasi et al, 2011;Tey et al, 2007), human CD20 (Vogler et al, 2010), and mutant human thymidylate kinase (mTMPK). The above causes cell sensitivity to the corresponding prodrugs: ganciclovir (GCV), nontoxic AP1903 drug (Hoyos et al, 2010), monoclonal antibody Rituximab, or zidovudine (AZT) (Sato et al, 2007).…”