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physical half-life of the radionuclide used. Thus, it may only be useful for the
initial distribution phase of administered cells.
24.5 Regulation of a Reporter Gene
The insertion of reporter genes is the alternative approach either through
incorporation of light-generating systems, such as luciferase (leaving aside
the practicality of clinical optical imaging in this case), or engineered to
express enzymes, such as a mutant herpes simplex virus type 1 thymidine
kinase (HSV1-sr39tk), which can be selectively imaged by administration of
[ 18 F]FHBG (9-[4- 18 (9-[4-18F-fluoro-3-(hydroxymethyl)butyl]guanine) and others [11]
or other radioactive compounds. Such approaches have been covered by FDA
guidances (as discussed here) [4] at least from the genetic point of view.
24.6 Toxicity Assessment
No matter which imaging mechanism is employed, the most important
concept that must be justified before first-in-man use is the risk/benefit
ratio. How does one establish the long-term toxic effects, if any, of labeling
such cells? These are issues that are not touched on in the published regu-
latory advice.
The mass of labeling agent administered with the cells is necessarily small
and is limited by the volume of cells. One might think that this minimizes
the risk and places the labeling agent in the microdosing category. However,
the “standard” methods of assessing the toxicity of a small molecule or bio-
logic are inappropriate in that they focus on systemic toxicity. The use of cells
labeled with iron particles is a case in point. Iron oxide-labeled dendritic
cells have been administered to melanoma patients and imaged by MRI [12].
The authors elected to use an approved iron particle and the normal phago-
cytic capacity of the immature dendritic cells. The particles in question are
approved in Europe and the United States but not for this indication. The
authors administered 7.5 × 10 6 cells containing 10-30 pg of iron per cell or a
total of 1-2 µg, which lies well within the mass amount limits of microdosing.
The study was performed in stage III melanoma patients, so a higher start-
ing dose (10% of the MTD) of iron may well be acceptable because the risk/
benefit ratio for oncology patients is different [13]. However, although the
safety profile of the iron particles after intravenous administration is estab-
lished, the toxicity to these particular cells is not, so what is the relevance of
a (whole-body) MTD in this case? The authors performed functional assays
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