Gene transfer applied to the modulation of alloreactivity

Area of Science:

• Immunology
• Gene Therapy
• Oncology

Background:

• Allogeneic hematopoietic stem cell transplantation (HSCT) faces challenges with graft-vs-host disease (GVHD), a severe complication mediated by donor T-cells.
• Ex vivo T-cell depletion prevents GVHD but impairs the graft-vs-leukemia (GVL) effect and increases graft rejection.
• A method is needed to control GVHD while preserving GVL and engraftment.

Purpose of the Study:

• To evaluate the safety and efficacy of ex vivo gene transfer of the herpes simplex thymidine kinase (HS-tk) suicide gene into donor T-cells for allogeneic HSCT.
• To enable selective in vivo T-cell depletion using ganciclovir (GCV) to manage GVHD.
• To preserve the GVL effect and enhance engraftment in HSCT recipients.

Main Methods:

• Retroviral-mediated gene transfer of HS-tk and neomycin resistance genes into human T-lymphocytes.
• Selection of gene-modified T-cells using G418.
• In vitro assessment of T-cell sensitivity to ganciclovir (GCV) and evaluation of bystander effects.
• Phase I clinical study involving infusion of HS-tk expressing T-cells with T-cell depleted marrow grafts in HLA-identical recipients.

Main Results:

• Retroviral transfer successfully engineered T-cells expressing HS-tk, demonstrating specific inhibition by GCV without significant bystander effects.
• The engineered T-cells showed selective depletion in the presence of GCV.
• The study is proceeding to a Phase I clinical trial to assess toxicity, survival, and GCV sensitivity in patients.

Conclusions:

• Ex vivo HS-tk gene transfer into donor T-cells offers a promising strategy for controlling GVHD post-allogeneic HSCT.
• This approach has the potential to mitigate GVHD, preserve the GVL effect, and improve engraftment.
• Successful implementation could expand the therapeutic use of alloreactivity in HSCT.