Suicide genes: monitoring cells in patients with a safety switch

Abstract

Clinical trials increasingly incorporate suicide genes either as direct lytic agents for tumors or as safety switches in therapies based on genetically modified cells. Suicide genes can also be used as non-invasive reporters to monitor the biological consequences of administering genetically modified cells to patients and gather information relevant to patient safety. These genes can monitor therapeutic outcomes addressable by early clinical intervention. As an example, our recent clinical trial used 18F-9-(4-fluoro-3-hydroxymethylbutyl)guanine (18FHBG) and positron emission tomography (PET)/CT scans to follow T cells transduced with herpes simplex virus thymidine kinase after administration to patients. Guided by preclinical data we ultimately hope to discern whether a particular pattern of transduced T cell migration within patients reflects early development of graft vs. host disease. Current difficulties in terms of choice of suicide gene, biodistribution of radiolabeled tracers in humans vs. animal models, and threshold levels of genetically modified cells needed for detection by PET/CT are discussed. As alternative suicide genes are developed, additional radiolabel probes suitable for imaging in patients should be considered.

Imaging grafted cells with [18F]FHBG using an optimized HSV1-TK mammalian expression vector in a brain injury rodent model

“…Different radioactive compounds are routinely injected in patients for clinical diagnosis. [ 18 F]FHBG appears to be an effective tool for obtaining biological information in a non-invasive manner and has been already tested in a clinical trial, in patient with leukaemia after infusion of Tcell genetically modified [ 7 , 8 ].…”

“…[ 18 F]FHBG is a PET imaging radiotracer that is easily transferrable to human applications [ 7 , 8 ]. PET scans allow radiolabelled markers and their interactions with biochemical processes to be imaged in living subjects.…”

[ 18 F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

“…Mice were imaged and scans were analyzed in the Washington University (WU) Preclinical PET/CT Imaging Facility with the assistance of Lori Strong, Nichole Fettig, Ann Stroncek, Amanda Roth, and Margaret Morris. The WU Cyclotron Facility prepared the 18 …”

“…those mice that eventually developed GvHD 18. By day 21, in this model, up to half of the animals injected i.v.…”

Editorial: Improving the safety of cell therapy products by suicide gene transfer

“…Although major contributions have been provided by clinical trials using HSV-tk-engineered T cells, a major issue remaining to be solved is related to the monitoring of GMCs in patients. In this article, Eissenberg et al ( 2014 ) suggest to use HSV-tk for monitoring functions in order to localize GMCs. Using 18 F-9-(4-fluoro-3-hydroxymethylbutyl) guanine ( 18 FHBG), it is possible to follow and monitor GMCs with PET/CT scans in order to know if cells reach their target.…”