2007
DOI: 10.1089/hum.2007.004
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A Model for Optimizing Adenoviral Delivery in Human Cancer Gene Therapy Trials

Abstract: Optimization of adenoviral delivery to the target volume is required for adenovirus-mediated cancer gene therapy to reach its maximal potential. The purpose of these studies was to develop a model of gene expression to improve adenovirus-mediated cancer gene therapy in the clinic. We measured the distribution of gene expression after a single deposit of a replication-competent adenovirus carrying the human sodium iodide symporter (hNIS) reporter gene was delivered to naive canine prostate and to human tumor xe… Show more

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Cited by 6 publications
(5 citation statements)
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“…NIS-mediated radiotracer uptake occurs in a viral dose-dependent manner, shown in both in vitro uptake assays and in vivo monitoring of mice administered escalating doses of NIS-expressing viruses. [ 15 , 31 , 40 , 41 , 43 , 45 , 48 , 49 , 59 , 71 ] Prior to induction of cytotoxicity, radiotracer uptake increases with viral dose, with some viruses showing a maximum level of uptake that plateaus above a certain multiplicity of infection in in vitro assays, suggesting a maximal level of NIS expression per cell can be achieved. [ 31 ] This may correlate with maximal infection burden, explaining why tumors in animals treated with low viral doses initially experience a slower increase in intratumoral radiotracer uptake relative to animals treated at higher doses.…”
Section: Nis-mediated Imaging and Treatment Strategymentioning
confidence: 99%
See 1 more Smart Citation
“…NIS-mediated radiotracer uptake occurs in a viral dose-dependent manner, shown in both in vitro uptake assays and in vivo monitoring of mice administered escalating doses of NIS-expressing viruses. [ 15 , 31 , 40 , 41 , 43 , 45 , 48 , 49 , 59 , 71 ] Prior to induction of cytotoxicity, radiotracer uptake increases with viral dose, with some viruses showing a maximum level of uptake that plateaus above a certain multiplicity of infection in in vitro assays, suggesting a maximal level of NIS expression per cell can be achieved. [ 31 ] This may correlate with maximal infection burden, explaining why tumors in animals treated with low viral doses initially experience a slower increase in intratumoral radiotracer uptake relative to animals treated at higher doses.…”
Section: Nis-mediated Imaging and Treatment Strategymentioning
confidence: 99%
“…[ 39 ] Predictive mathematical models, such as those using VSV to target multiple myeloma and adenovirus to target prostate cancer, can be generated or improved upon using information from molecular imaging to facilitate dose optimization for complete tumor coverage with gene expression. [ 71 , 78 ] For oncolytic viruses with limited clinical efficacy, combination treatments may be beneficial and molecular imaging of viral spread in tumors could provide unique information to rationalize combination treatments. For example, the NIS transgene also confers the potential for radiovirotherapy to improve tumor response relative to oncolytic virus alone in preclinical studies.…”
Section: Expert Opinionmentioning
confidence: 99%
“…Virus-based suicide-gene therapies are based primarily on the premise that tumor cells expressing the suicide genes will be rendered sensitive to specific pharmacologic agents thereby providing a local cytotoxic effect and improving the therapeutic index [ 78 , 84 , 85 , 95 103 ]. Delivery of the virus to the tumor is usually accomplished by direct intra-tumoral or systemic injection of a viral vector containing the suicide gene.…”
Section: Gene Therapy Clinical Trials At Henry Ford Healthmentioning
confidence: 99%
“…These investigators used a replication-competent adenovirus encoding a yeast cytosine deaminase (yCD)--herpes simplex virus thymidine kinase ( mut TK SR39 ) fusion protein and a second transgene encoding NIS in mouse xenograft and dog prostate models. This same group of investigators went on to publish two additional studies to further develop and optimize this adenovirus-mediated therapy protocol in small and large animal models [94, 119] and ultimately to demonstrate the safety and feasibility of NIS and 99m TcO 4 SPECT/CT as an imaging reporter system in humans [120, 121]. …”
Section: The Role Of Nis As An Imaging Reporter Genementioning
confidence: 99%
“…While in other cells, a region of low MOI infection combined with substantial amplification could result in a similar imaging signal as a high MOI infection. In order to deal with these practical issues, Barton et al , [66, 119, 121] introduced the concept of gene expression volume (GEV, with units of cm 3 ) and the gene expression unit (GE, which equals the GEV times the ratio of imaging intensity in the GEV to that of blood). For example, a region of interest signal of 1 cm 3 with a mean calculated probe concentration of 3 times that of the blood would equal 3 GE units.…”
Section: Relationship Between Imaging Activity and Fraction Of Nis-exmentioning
confidence: 99%