Enhancing Expression of Functional Human Sodium Iodide Symporter and Somatostatin Receptor in Recombinant Oncolytic Vaccinia Virus for In Vivo Imaging of Tumors

Abstract

Oncolytic virus (OV) therapy has emerged as a novel tool in our therapeutic arsenals for fighting cancer. As a live biologic agent, OV has the ability to target and selectively amplify at the tumor sites. We have reported that a vaccinia-based OV (Pexa-Vec) has shown good efficacy in preclinical models and in clinical trials. To give an additional tool to clinicians to allow both treatment of the tumor and improved visualization of tumor margins, we developed new viral-based platforms with 2 specific gene reporters. Methods: We incorporated the human sodium iodide symporter (hNIS) and the human somatostatin receptor 2 (hSSR2) in the vaccinia-based OV and tested viral constructs for their abilities to track and treat tumor development in vivo. Results: Early and high-level expression of hNIS is detrimental to the recombinant virus, leading to the aggregation of hNIS protein and early cell death. Putting hNIS under a late synthetic promoter allowed a higher functional expression of the protein and much stronger 123 I or 99 Tc uptake. In vivo, the hNIS-containing virus infected and amplified in the tumor site, showing a better efficacy than the parental virus. The hNIS expression at the tumor site allowed for the imaging of viral infection and tumor regression. Similarly, hSSR2-containing OV vaccinia infected and lysed cancer cells. Conclusion: When tumor-bearing mice were given hNIS-and hSSR2-containing OV, 99 Tc and 111 In signals coalesced at the tumor, highlighting the power of using these viruses for tumor diagnosis and treatment.

Recombinant Newcastle disease virus expressing human IFN‐λ1 (rL‐hIFN‐λ1)‐induced apoptosis of A549 cells is connected to endoplasmic reticulum stress pathways

“…This is partially attributable to the limited therapeutic efficacy of surgery, radiation, and chemotherapy in lung cancer. Fortunately, accumulating evidence has revealed the significant role of oncolytic tumor therapy …”

Delivery and Biosafety of Oncolytic Virotherapy

“…Human sodium iodide synergistic transporter protein (hNIS) was combined with human somatostatin receptor 2 (hSSR2) to engineer oncolytic viruses. After systemic administration of this virus, radioisotopes ( 99 Tc and 131 I) were administered, resulting in accumulation of the isotopes in the tumor mass, thereby enabling the tumor to be observed and located in a mouse model using a SPECT/CT imaging system (18). A combination of an exogenous lysine-rich protein (LRP) gene with the HSV genome can be used to image tumors by MRI because this construct changes the magnetic field associated with the metabolism rate of the tumors (19).…”

“…A combination of an exogenous lysine-rich protein (LRP) gene with the HSV genome can be used to image tumors by MRI because this construct changes the magnetic field associated with the metabolism rate of the tumors (19). The accurate imaging of tumors by oncolytic viruses has shown broad application prospects for early diagnosis and localization and visualization of tumors (18,19).…”

The importance of imaging strategies for pre-clinical and clinical in vivo distribution of oncolytic viruses

“… 39 Following first cloning procedures, several in vivo experiments assessed NIS expression and its use in non-thyroid tissue, notably in tumor tissue. 40 …”