HSV-TK Gene Transfer into Donor Lymphocytes for Control of Allogeneic Graft-Versus-Leukemia

Abstract

In allogeneic bone marrow transplantation (allo-BMT), donor lymphocytes play a central therapeutic role in both graft-versus-leukemia (GvL) and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GvHD). Eight patients who relapsed or developed Epstein-Barr virus-induced lymphoma after T cell-depleted BMT were then treated with donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-TK) suicide gene. The transduced lymphocytes survived for up to 12 months, resulting in antitumor activity in five patients. Three patients developed GvHD, which could be effectively controlled by ganciclovir-induced elimination of the transduced cells. These data show that genetic manipulation of donor lymphocytes may increase the efficacy and safety of allo-BMT and expand its application to a larger number of patients.

Homing and survival of thymidine kinase-transduced human T cells in NOD/SCID mice

“…Interestingly, it is worth noting that some cases of GvHD have been reported in patients receiving tktransduced lymphocytes for leukemia relapse after allogeneic stem cell transplantation. 10 The present observation may throw some light on the biological mechanisms underlying the failure of GCV treatment.…”

“…9,10 In the present report, engraftment of the human T lymphocytes in NOD /SCID mice was assessed using freshly engineered T lymphocytes. CD45 + /CD3 + flowcytometric analysis, PCR detection of NeoR gene, and immunohistological staining of mouse tissues (spleen and liver) with antibodies specific for human CD3 antigen showed that engraftment was successful.…”

“…9 Donor-transduced T lymphocytes are also used to prevent and treat leukemia relapse after bone marrow transplants. 10 However, no data are available on the homing of transduced T lymphocytes in both animal models and humans. In order to further understand the behavior and fate of tk -transduced T cells, we injected engineered T cells in NOD /SCID mice and monitored them by means of cytofluorimetric analysis, polymerase chain reaction (PCR ), and immunohistological studies.…”

A self-immunomodulating myoblast cell line for erythropoietin delivery

“…Some previous reports have described immune responses associated with the introduction of selectable marker genes in immunocompetent hosts. [25][26][27][28] The acute rejection process observed in both syngeneic and allogeneic recipients suggests that C 2 C 12 myoblasts constitute a stringent model of cell transplantation. The expression of class I major histocompatibility complexes (MHC) in response to ␥IFN stimulation accounts for the immunogenicity of the C 2 C 12 cell line (data not shown).…”

The application of gene therapy in autoimmune diseases

“…This was recently demonstrated in human trials using the thymidine kinase gene. 23 Currently, the most efficient way to introduce genes into lymphoid cells is via transduction, utilizing viral vectors. The most widely studied and utilized viral vectors in humans are murine retrovirus derived.…”