Herpes simplex thymidine kinase gene-transduced donor lymphocyte infusions

Area of Science:

• Immunotherapy
• Hematologic Oncology
• Gene Therapy

Background:

• Allogeneic hematopoietic stem cell transplantation (HSCT) relies on donor lymphocytes for graft-vs-leukemia/lymphoma (GVL) effects but risks graft-vs-host disease (GVHD).
• Engineering donor lymphocytes with herpes simplex thymidine kinase (HSVtk) confers sensitivity to ganciclovir (GCV), enabling selective elimination.

Purpose of the Study:

• To evaluate the safety and efficacy of HSVtk-gene-modified donor lymphocyte infusions (DLI) in patients with relapsed hematologic malignancies.
• To determine if GCV administration can abrogate GVHD while preserving the GVL effect.

Main Methods:

• Nine patients with relapsed hematologic malignancies post-HSCT received HSVtk-transduced DLI.
• Lymphocytes were activated, transduced with HSVtk, selected, and expanded before infusion.

Main Results:

• No dose-limiting toxicities were observed; no correlation between CD3(+) cell dose and GVHD/GVL was found.
• One patient with cutaneous T-cell lymphoma (CTCL) developed GVHD and showed an anti-tumor response; GVHD resolved upon GCV infusion.
• Limited responses were observed in other patients with acute myelogenous leukemia (AML), lymphoma, and chronic myelogenous leukemia (CML).

Conclusions:

• HSVtk-DLI demonstrates potential for in vivo anti-tumor activity and controllable GVHD via GCV treatment.
• Further technical refinement is needed, but transient GVL/GVHD induction via HSVtk-DLI may offer a future strategy to mitigate HSCT complications.