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Suicide genes: monitoring cells in patients with a safety switch.

Eissenberg LG, Rettig M, Dehdashti F, Piwnica-Worms D, DiPersio JF - Front Pharmacol (2014)

Bottom Line: These genes can monitor therapeutic outcomes addressable by early clinical intervention.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis MO, USA.

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 (18)F-9-(4-fluoro-3-hydroxymethylbutyl)guanine ((18)FHBG) 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.

No MeSH data available.


Related in: MedlinePlus

18F-FHBG-PET/CT scans of patients. Under FDA IND #11917 (clinicaltrials.gov #NCT00871702) patients received 0.1–1.3 × 106 purified allogeneic CD34-TK75-transduced cells/kg as a donor lymphocyte infusion (DLI). 18F-FHBG-PET/CT scans were performed at baseline before DLI, and on ∼days +14 and +30 after DLI. Anterior and posterior reprojection images of patient TK05 are shown. Scans were made 60 min after administration of 18F-FHBG and show a normal distribution of the radiotracer. No reproducible difference was detected between the baseline and later scans for any patient. TK05 did not develop graft vs. host disease (GvHD).
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Figure 1: 18F-FHBG-PET/CT scans of patients. Under FDA IND #11917 (clinicaltrials.gov #NCT00871702) patients received 0.1–1.3 × 106 purified allogeneic CD34-TK75-transduced cells/kg as a donor lymphocyte infusion (DLI). 18F-FHBG-PET/CT scans were performed at baseline before DLI, and on ∼days +14 and +30 after DLI. Anterior and posterior reprojection images of patient TK05 are shown. Scans were made 60 min after administration of 18F-FHBG and show a normal distribution of the radiotracer. No reproducible difference was detected between the baseline and later scans for any patient. TK05 did not develop graft vs. host disease (GvHD).

Mentions: Only one of our six imaged patients developed GvHD (day 64) potentially attributable to the genetically modified T cells. Unfortunately no discernable difference was observed between the biodistribution of 18F-FHBG in this or any other patient at baseline and later time points (Figure 1). We used a portion of the same CD34-TK75 transduced donor T cells and 18F-FHBG prepared for the patients under GMP conditions in a parallel transplant of 2 NOD-SCIDg-/-(NSG) mice for each patient. As expected the xenogeneic CD34-TK75 transduced T cells induced GvHD in NSG mice, and the 18F-FHBG-microPET/CT scans revealed transduced T cells in their thymic region (Figure 2). We previously demonstrated by BLI that this site is one of the preferred locations for migration and expansion of human T cells during xenogeneic GvHD (Nervi et al., 2007). Our current data recapitualted this distinctive migration pattern and also reflects the feasibility of in-house cGMP production of both functional transduced suicide gene expressing human T cells and 18F-FHBG.


Suicide genes: monitoring cells in patients with a safety switch.

Eissenberg LG, Rettig M, Dehdashti F, Piwnica-Worms D, DiPersio JF - Front Pharmacol (2014)

18F-FHBG-PET/CT scans of patients. Under FDA IND #11917 (clinicaltrials.gov #NCT00871702) patients received 0.1–1.3 × 106 purified allogeneic CD34-TK75-transduced cells/kg as a donor lymphocyte infusion (DLI). 18F-FHBG-PET/CT scans were performed at baseline before DLI, and on ∼days +14 and +30 after DLI. Anterior and posterior reprojection images of patient TK05 are shown. Scans were made 60 min after administration of 18F-FHBG and show a normal distribution of the radiotracer. No reproducible difference was detected between the baseline and later scans for any patient. TK05 did not develop graft vs. host disease (GvHD).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222135&req=5

Figure 1: 18F-FHBG-PET/CT scans of patients. Under FDA IND #11917 (clinicaltrials.gov #NCT00871702) patients received 0.1–1.3 × 106 purified allogeneic CD34-TK75-transduced cells/kg as a donor lymphocyte infusion (DLI). 18F-FHBG-PET/CT scans were performed at baseline before DLI, and on ∼days +14 and +30 after DLI. Anterior and posterior reprojection images of patient TK05 are shown. Scans were made 60 min after administration of 18F-FHBG and show a normal distribution of the radiotracer. No reproducible difference was detected between the baseline and later scans for any patient. TK05 did not develop graft vs. host disease (GvHD).
Mentions: Only one of our six imaged patients developed GvHD (day 64) potentially attributable to the genetically modified T cells. Unfortunately no discernable difference was observed between the biodistribution of 18F-FHBG in this or any other patient at baseline and later time points (Figure 1). We used a portion of the same CD34-TK75 transduced donor T cells and 18F-FHBG prepared for the patients under GMP conditions in a parallel transplant of 2 NOD-SCIDg-/-(NSG) mice for each patient. As expected the xenogeneic CD34-TK75 transduced T cells induced GvHD in NSG mice, and the 18F-FHBG-microPET/CT scans revealed transduced T cells in their thymic region (Figure 2). We previously demonstrated by BLI that this site is one of the preferred locations for migration and expansion of human T cells during xenogeneic GvHD (Nervi et al., 2007). Our current data recapitualted this distinctive migration pattern and also reflects the feasibility of in-house cGMP production of both functional transduced suicide gene expressing human T cells and 18F-FHBG.

Bottom Line: These genes can monitor therapeutic outcomes addressable by early clinical intervention.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis MO, USA.

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 (18)F-9-(4-fluoro-3-hydroxymethylbutyl)guanine ((18)FHBG) 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.

No MeSH data available.


Related in: MedlinePlus