Improving the safety of cell therapy with the TK-suicide gene

Abstract

While opening new frontiers for the cure of malignant and non-malignant diseases, the increasing use of cell therapy poses also several new challenges related to the safety of a living drug. The most effective and consolidated cell therapy approach is allogeneic hematopoietic stem cell transplantation (HSCT), the only cure for several patients with high-risk hematological malignancies. The potential of allogeneic HSCT is strictly dependent on the donor immune system, particularly on alloreactive T lymphocytes, that promote the beneficial graft-versus-tumor effect (GvT), but may also trigger the detrimental graft-versus-host-disease (GvHD). Gene transfer technologies allow to manipulate donor T-cells to enforce GvT and foster immune reconstitution, while avoiding or controlling GvHD. The suicide gene approach is based on the transfer of a suicide gene into donor lymphocytes, for a safe infusion of a wide T-cell repertoire, that might be selectively controlled in vivo in case of GvHD. The herpes simplex virus thymidine kinase (HSV-TK) is the suicide gene most extensively tested in humans. Expression of HSV-TK in donor lymphocytes confers lethal sensitivity to the anti-herpes drug, ganciclovir. Progressive improvements in suicide genes, vector technology and transduction protocols have allowed to overcome the toxicity of GvHD while preserving the antitumor efficacy of allogeneic HSCT. Several phase I-II clinical trials in the last 20 years document the safety and the efficacy of HSV-TK approach, able to maintain its clear value over the last decades, in the rapidly progressing horizon of cancer cellular therapy.

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

“…The HSV-TK strategy is currently under evaluation in a phase III clinical trial in patients undergoing haploidentical HSCT for high-risk acute leukemia. Preliminary results of this ongoing trial confirmed the potential clinical benefit of the T-cell gene-transfer technology integrated with T-cell depletion haploidentical HSCT, and highlighted the role of early immune reconstitution as a surrogate endpoint for survival outcomes and the dose-related antileukemic effects of TK [58].…”

“…Several clinical trials in the last 20 years documented the safety and the efficacy of the HSV-TK approach and established its important role in cellular therapy against cancer. Recently developed gene therapies have improved immune effector cell survival, homing, function, safety, and specificity using high-avidity tumor-reactive T-cell receptors (TCRs) or chimeric antigen receptors, and suicide gene therapy has been reappraised with the goal of avoiding or controlling the toxic effects induced by these innovative therapies [58].…”

“…In this setting, the risk of GvHD is particularly high due to the immunological disparity between donor and host [58,61]. In a phase I/II, multicenter, non-randomized trial of haploidentical stem-cell transplantation, and retrovirally HSV-TK-transduced donor lymphocytes (TK cells) were administered after transplantation.…”

Characterization of the nitroreductase/metronidazole suicide gene system as a safeguard for cell based therapies

“…HSV-tk has a high affinity for ganciclovir (GCV) 6 . GCV and various other cellular kinases phosphorylate HSV-tk into a triphosphate derivative, which mimics guanosine and is able to incorporate itself into DNA.…”

Coadministration of posaconazole and sirolimus in allogeneic hematopoietic stem cell transplant recipients

“…Due to recent extension of HSCT to patients at high risk of IFI (high-risk diseases, older patients and/or with comorbidities) with novel HSCT platforms (novel conditioning regimens, haploidentical or cord blood HSCT, CD34+ stem cell selection/T-cell depletion in vitro or in vivo), 12 antifungal prophylaxis has been a 'moving target', so reaching a consensus has proved difficult. Thus, posaconazole has an important role as prophylactic and salvage treatment of IFIs, although its variable bioavailability remains an important clinical concern.…”