) We propose to assess transgene expression by non-invasive imaging in patients undergoing gene therapy. Four separate components, involving four different clinical trials, are included in this proposal in order to provide a broad clinical spectrum for assessing the benefits and limitations of imaging transgene expression in a clinical setting. Three different viral vectors (adenovirus, Herpes Simplex Virus, and retrovirus) will be used in these clinical trials and this will provide the opportunity to obtain comparable imaging data for each of the three vectors. Two of the components will involve patients in existing clinical trials at Mount Sinai Medical School in New York. One clinical trial involves patients with hepatic metastases from colorectal cancer, and the other involves patients with local prostate cancer; both trials involve direct intratumoral injection of an adenoviral vector (ADV-tk) expressing the Herpes Simplex Virus thymidine kinase gene (HSV1-tk), followed by intravenous ganciclovir treatment. The third and fourth components will involve both preclinical and clinical imaging studies at MSKCC, and will also involve patients with colorectal hepatic metastases. The third component involves an experimental treatment protocol where a replication restricted Herpes Simple Virus type-1 (mHSV1; G207 or R7020) is injected into the hepatic artery to induce selective cytolysis of dividing tumor cells (hepatic metastases). The fourth component will involve hepatic artery injection of a retrovirus (DCSV or SFG) containing a fusion gene which includes dihydrofolate reductase (DHFR) and HSV1-tk cDNA. The treatment rationale is based on data showing that exposure of transduced tumor cells to trimethotrexate (TMTX) will lead to amplification of DHFR and consequently, to amplification of the HSV1-TK as well; in turn, this will make the transduced cells more sensitive to ganciclovir. HSV-TK imaging will be performed using positron emission tomography (PET) and 124-I labeled FIAU (2'-fluoro-1-beta-D-arabinofuranosyl-5-iodo-uracil); we have previously demonstrated that [124I]-FIAU PET imaging of HSV-TK activity following retroviral and adenoviral (ADV-tk) transduction is feasible, selective and quantitative. The preclinical studies in this proposal will: 1) extend these studies and demonstrate selective vector imaging, 2) provide a comparison between mHSV1 (G207 and R7020) and retroviral (DCSV and SFG) vectors in appropriate experimental animal models, and 3) provide imaging data that could support and justify the initiation of clinical trials. The clinical studies are the focus of this proposal and will demonstrate that noninvasive imaging of transgene expression in target tissue can be used to monitor and facilitate the evaluation of gene therapy by defining the location, magnitude and persistence of transgene expression over time. It would also provide the opportunity to assess the spread of the vector to nontarget tissue and organs using whole body imaging techniques, and it could define the optimal time and duration of time for effective pro-drug administration.
| Serganova, Inna; Humm, John; Ling, Clifton et al. (2006) Tumor hypoxia imaging. Clin Cancer Res 12:5260-4 |
