Clinical Impact of Suicide Gene Therapy in Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-SCT) from an HLA-matched related or unrelated donor is a curative option for patients with high-risk hematological diseases. In the absence of a matched donor, patients have been offered investigational transplantation strategies such as umbilical cord blood SCT or family haploidentical SCT. Besides the activity of the conditioning regimen, most of the antileukemic potential of allo-SCT relies on alloreactivity, promoted by donor lymphocytes reacting against patient-specific antigens, such as minor and major histocompatibility antigens, ultimately translating into cancer immunotherapy. Unfortunately, alloreactivity is also responsible for the most serious and frequent complication of allo-SCT: graft-versus-host-disease (GvHD). The risk of GvHD increases with the level of HLA disparity between host and donor, and leads to impaired quality of life and reduced survival expectancy, particularly among patients receiving transplants from HLA-mismatched donors. Gene transfer technologies are promising tools to manipulate donor T cell immunity to enforce the graft-versus-tumor effect, to promote functional immune reconstitution (graft vs. infection), and to prevent or control GvHD. To this purpose, several cell and gene transfer approaches have been investigated at the preclinical level, and are being implemented in clinical trials. Suicide gene therapy is to date the most extensive clinical application of T cell-based gene therapy. In several phase I-II clinical studies conducted worldwide this approach proved highly feasible, safe, and effective in promoting a dynamic and patient-specific modulation of alloreactivity. This review focuses on this approach.

Long-term in vivo monitoring of mouse and human hematopoietic stem cell engraftment with a human positron emission tomography reporter gene

“…hdCK3mut provides an alternative PET reporter gene to sr39TK. One concern for alternate reporters is the loss of suicide gene function, which is gained when HSV1-TK and mutants are used (40). Gene transfer of HSV1-TK into select cell populations allowed for targeted cytotoxicity when treated with FDAapproved acycloguanosine-based antiviral drugs such as ganciclovir (41).…”

Development of gene therapy for blood disorders: an update

“…A number of genetic systems have been used or explored experimentally. 68 Two have been tested in clinical trials, 1 with a vector having the thymidine kinase gene, and posttreatment is with ganciclovir. 68 The other system involves caspase-9.…”

“…68 Two have been tested in clinical trials, 1 with a vector having the thymidine kinase gene, and posttreatment is with ganciclovir. 68 The other system involves caspase-9. 69 T cells containing this gene can be abrogated using a dimerizing drug (AP1903).…”

Next-generation leukemia immunotherapy

“…29,31,32 Ag spreading can even extend to B-cell responses against cell-surface molecules. 30 Nevertheless, an alternative approach to leukemia immunotherapy pioneered by Bordignon et al 107,108 has also yielded promising results: injection of polyclonal allogeneic lymphocytes transduced to express a suicide gene. Expression of a suicide gene confers to cells sensitivity to a molecule (prodrug) that is nontoxic to nonexpressing cells.…”

“…107,109 Therefore, several new cell and gene transfer approaches are being evaluated in phase 1-2 clinical studies. 108 …”