Viral dose, radioiodide uptake, and delayed efflux in adenovirus-mediated NIS radiovirotherapy correlates with treatment efficacy

Abstract

We have constructed a prostate tumor specific conditionally replicating adenovirus (CRAd), named Ad5PB_RSV-NIS that expresses the human sodium iodine symporter gene (hNIS). LNCaP tumors were established in nude mice and infected with this CRAd to study tumor viral spread, NIS expression, and efficacy. Using quantitative polymerase chain reaction (QPCR) we found a linear correlation between the viral dose and viral genome copy numbers recovered after tumor infection. Confocal microscopy showed a linear correlation between adenovirus density and NIS expression. Radioiodine uptake vs. virus dose-response curves revealed that the dose response curve was not linear and displayed a lower threshold of detection at 107 vp and an upper plateau of uptake at 1011 vp. The outcome of radiovirotherapy was highly dependent upon viral dose. At 1010 vp no significant differences were observed between virotherapy alone or radiovirotherapy. However, when radioiodine therapy was combined with virotherapy at a dose of 1011 vp, significant improvement in survival was observed, indicating a relationship between viral dose-response uptake and the efficacy of radiovirotherapy. The reasons behind the differences in radioiodine therapy efficacy can be ascribed to more efficient viral tumor spread and a decrease in the rate of radioisotope efflux. Our results have important implications regarding the desirables and undesirable characteristics of vectors for clinical translation of virus-mediated NIS transfer therapy

Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

“…4 Cloning of NIS in 1996, 5,6 as one of the major milestones in thyroidology in the last 20 years, opened the way for the use of this potent dual reporter and therapy gene concept in the treatment of a broad range of cancer types by targeting NIS to nonthyroidal cancer cells. Extensive characterization of the applicability of NIS as a diagnostic and therapeutic gene by several research groups, including our own, [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] revealed NIS to be a remarkable and powerful tool for detecting and treating different extrathyroidal cancer types, even in metastatic disease. [25][26][27][28] The high incidence of hepatocellular carcinoma (HCC) as a result of a late diagnosis and a poor prognosis along with limited treatment strategies urgently requires the development of new treatment strategies.…”

Sodium iodide symporter (NIS) in extrathyroidal malignancies: focus on breast and urological cancer

“…A NIS gene delivered with an adenovirus vector and a tissue-specific gene promoter, the prostate-specific antigen gene (PSA) promoter, conferred efficient functional NIS expression in prostate cancer xenografts [ 79 , 80 ]. In a recent report, Trujillo and coworkers, by using a prostate tumor–specific CRAd in a xenograft model of prostate cancer, demonstrated that the efficacy of radioiodide therapy depends mainly on an efficient viral tumor spread and a decrease in the rate of the efflux of radioisotope [ 81 ]. To achieve synergistic or additive cytotoxic effects, combined treatments with NIS gene therapy and a tumor targeting strategy, such as utilization of an oncolytic vector [ 82 ], are also under experimentation.…”

Monitoring of Biodistribution and Persistence of Conditionally Replicative Adenovirus in a Murine Model of Ovarian Cancer Using Capsid-Incorporated mCherry and Expression of Human Somatostatin Receptor Subtype 2 Gene

“…Although SSTR2 was not employed previously for CRAd monitoring, several groups reported the use of human NIS as a reporter gene for imaging of various CRAd agents following intratumoral injection in animal models of colorectal, 63,65 prostate, 60,66,67,[94][95][96] and peritoneal ovarian cancer. 62 These SPECT imaging studies show that human NIS expression reaches a peak 2 to 4 days after intratumoral injection, followed by a sharp disappearance of human NISdependent accumulation of radiotracer.…”