Abstract
IntroductionOncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS.MethodsGLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide 131I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP) and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via 124I-positron emission tomography (PET). Detection of systemic administration of virus was investigated with both 124I-PET and 99m-technecium gamma-scintigraphy.ResultsGLV-1h153 successfully facilitated time-dependent intracellular uptake of 131I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P<0.05). In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 109 plaque-forming unit (PFU)/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean %ID/gm of 3.82±0.46 (P<0.05) 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV-1h153-infected tumors were detected via 124I-PET and 99m-technecium-scintigraphy.ConclusionGLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic cancer cells, facilitating detection by PET with both intratumoral and systemic administration. Therefore, GLV-1h153 is a promising candidate for the noninvasive imaging of virotherapy and warrants further study into longterm monitoring of virotherapy and potential radiocombination therapies with this treatment and imaging modality.
Highlights
Oncolytic viruses show promise for treating cancer
Vaccinia’s large 192-kb genome [2] enables a large amount of foreign DNA to be incorporated without significantly reducing the replication efficiency of the virus, which has been shown to be the case with some adenoviruses [3]
We have previously reported on the construction and generation of a novel attenuated replication-competent vaccinia virus (VACV), GLV-1h153, a derivative of parental virus GLV-1h68 engineered to carry the human sodium iodide symporter [16]. hNIS, an intrinsic plasma membrane protein, facilitates transport of several carrier-free radiotracers such as radioiodine and technecium-pertechnetate (99mTcO4) [17]
Summary
Oncolytic viruses show promise for treating cancer. to assess therapy and potential toxicity, a noninvasive imaging modality is needed. Oncolytic viral therapies have shown such promise in preclinical trials as a novel cancer treatment modality, that several phase I and II trials are already underway [1]. Vaccinia’s large 192-kb genome [2] enables a large amount of foreign DNA to be incorporated without significantly reducing the replication efficiency of the virus, which has been shown to be the case with some adenoviruses [3]. It has fast and efficient replication, and cytoplasmic replication of the virus lessens the chance of recombination or integration of viral DNA into cells [3,4]. Furthering its safety profile, vaccinia immunoglobulin and antiviral drugs are available if needed [15]
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