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

Abstract

The infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene (TK-cells) is a promising strategy for the treatment of hematologic malignancies relapsing after allogeneic hematopoietic stem cell transplantation. Here we report the results of a phase I clinical trial designed to examine the feasibility, safety, and efficacy of donor lymphocyte infusion (DLI) of TK-cells. Three patients (two with malignant lymphomas, one with acute myeloid leukemia) were enrolled in the trial and received a single DLI of 1 × 10(7) or 5 × 10(7) TK-cells/kg. No local or systemic toxicity related to the gene-transfer procedure was observed. Two patients achieved stable disease. No patient had severe graft-versus-host disease requiring systemic steroid and/or ganciclovir administration. TK-cells were detected in the peripheral blood of all three patients by PCR, but did not persist longer than 28 days. Analysis of cytotoxic T lymphocyte activity detected no immune response against TK-cells by the recipient's own T cells. Flow cytometric analysis showed low proliferative activity and cytotoxic function of TK-cells. In conclusion, DLI of TK-cells was safely performed in all three patients. Our analysis suggests the probable cause of rapid disappearance of TK-cells to be insufficient in vivo expansion of TK-cells in these patients.

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT

“…There was no local or systemic toxicity related to infusion, and no severe GVHD requiring systemic steroid and/or ganciclovir administration. 95 These results suggest that infusion of TK cells might be beneficial to facilitate immune reconstitution, augmenting GVL effect, with GVHD and its associated mortality being controllable.…”

“…19 The expression of herpes simplex thymidine kinase suicide gene was confirmed to promote immune reconstitution and GVT effect, and reduce risk of GVHD in DLI. 95 Moreover, ganciclovir can be given to abort GVHD when necessary. Ciceri et al 96 performed a multicenter non-randomized phase I-II study that 28 patients undergoing haploidentical SCTs received donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) starting 28 days after transplantation.…”

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

“…DLI of TK cells was safely performed in a total of eight patients. However, these TK cells disappeared rapidly, probably due to their insufficient in vivo expansion in these patients [77,78]. A comparison of onset with remission of acute GVHD confirmed that TK cells were predominantly eliminated and that proliferative CD8(+) non-TK cells were also depleted in response to ganciclovir administration.…”

“…With the long-term prophylactic administration of acyclovir, TK cells expanded oligoclonally, and the frequency of splice variants of TK cells increased. Known cancer-associated genes were not evident near the oligoclonally expanded HSV-TK insertion sites [78,79].…”

Donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene: detailed immunological function following add-back after haplo-identical transplantation

“…Each TCR Vb segment was amplified with one of the 24 Vb subfamilyespecific primers and a Cb primer. The sequences of primers Cb and Vb1 to 24 and spectratyping analysis was performed as reported previously [19]. The amplified PCR products were size-fractionated by capillary gel electrophoresis with the use of an ABI model 3130 Genetic Analyzer, and data were analyzed with the use of GeneMapper software v4.0 (Applied Biosystems).…”