A Vaccinia Virus Encoding the Human Sodium Iodide Symporter Facilitates Long-Term Image Monitoring of Virotherapy and Targeted Radiotherapy of Pancreatic Cancer

Abstract

To assess therapeutic response and potential toxicity of oncolytic virotherapy, a noninvasive, deep-tissue imaging modality is needed. This study aimed to assess the feasibility, parameters, and determining factors of serial imaging and long-term monitoring of virotherapy and the therapeutic response of pancreatic cancer xenografts treated with a vaccinia virus carrying the human sodium iodide symporter GLV-1h153. Methods: Pancreatic cancer xenografts (PANC-1) in nude mice were treated systemically or intratumorally with GLV-1h153 and serially imaged using 124 I PET at 1, 2, 3, and 5 wk after viral injection. Signal intensity was compared with tumor therapeutic response and optical imaging, and tumors were histologically analyzed for morphology and the presence of virus. Autoradiography was performed using technetium-pertechnetate and g-scintigraphy to assess determining factors for radiouptake in tumors. Finally, the enhanced therapeutic effect of combination therapy with GLV-1h153 and systemic radioiodine was assessed. Results: GLV-1h153 successfully facilitated serial long-term imaging of virotherapy, with PET signal intensity correlating to tumor response. GLV-1h153 colonization of tumors mediated radioiodine uptake at potentially therapeutic doses. Successful radiouptake required the presence of virus, adequate blood flow, and viable tissue, whereas loss of signal intensity was linked to tumor death and necrosis. Finally, combining systemically administered GLV1h153 and 131 I led to enhanced tumor kill when compared with virus or 131 I alone (P , 0.01). Conclusion: GLV-1h153 is a promising oncolytic agent for the treatment, long-term imaging, and monitoring of therapeutic response in a xenograft model of pancreatic cancer. GLV-1h153 provided insight into tumor biologic activity and facilitated enhanced tumor kill when combined with systemic targeted radiotherapy. These results warrant further investigation into parameters and potential synergistic effects of combination therapy.

The Sodium/Iodide Symporter (NIS): Molecular Physiology and Preclinical and Clinical Applications

“…After 48 h, I − accumulation decreased, NIS was no longer detectable at the plasma membrane, and the cells were dying (128). Haddad and colleagues (129) sequentially imaged a pancreatic tumor infected with a VV encoding NIS. They monitored NIS expression using radiotracer accumulation and IHC in explanted tumors at different stages of infection, observing that cell death was linked to decreased I − uptake.…”

Molecular network, pathway and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy

“…[5][6][7] Conditionally replicating viruses have been gaining increasing attention for their ability to kill tumor cells by oncolysis and apoptosis, and hence, this attenuated strain has shown promise as a selective anticancer agent. 5 We constructed a new virus which had three nonessential viral genes deleted and replaced with GFP, β-galactosidase, and the hNIS genes, creating GLV-1h153.…”

“…Several databases investigating genes associated with poxvirus infection have been established, such as the virus pathogen database and analysis resource (ViPR), 5 the poxvirus bioinformatics resource center, 6 the poxvirus proteomics database, 7 as well as literature addressing detection of and identification of different strains of orthopoxvirus. 1,[29][30][31][32] Although these databases were aimed mainly at the risk of bioterrorism or possible virus pandemic, information from these databases may be crucial to better understand virus behavior for oncotherapy.…”

An Oncolytic Vaccinia Virus Expressing the Human Sodium Iodine Symporter Prolongs Survival and Facilitates SPECT/CT Imaging in an Orthotopic Model of Malignant Pleural Mesothelioma

“…11 For these studies, we have modified the GLV-1h68 virus to carry hNIS, an imageable gene in an attempt to produce a therapeutic virus that we may be tracked by noninvasive imaging. We have previously published our success in utilizing this viral construct to both treat and provide real-time, non-invasive imaging of thyroid 12 , pancreatic 13 and triple negative breast cancer (TNBC) xenografts 14 . Most recently, we have demonstrated that GLV-1h153 can treat orthotopic TNBC underline tumors, prevent metastasis, and facilitate 131 I imaging of positive surgical margins after resection.…”