In Vivo Estimation of Oncolytic Virus Populations within Tumors

Abstract

The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of data has made difficult parametrization of these models. To tackle this problem, we studied the and spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression and implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution These data suggest that methods that enable quantitation of anisotropies are required for continuing development of oncolytic virotherapy. These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses .

Delivery and Biosafety of Oncolytic Virotherapy

“…Maintaining the concentration of oncolytic virus in the target site is a crucial advantage of intratumoral delivery, and researchers tend to observe more definite therapeutic effects with this method (39)(40)(41). Intratumoral delivery enables researchers to control the precise concentration of the oncolytic virus at the tumor site and to compare the results of in vitro experiments with those of in vivo studies (26,42,43). However, the risks and expenses associated with the complex procedures involved in intratumoral delivery make repeat dosing in vivo difficult.…”

“…Choi et al proved that CF33 (a novel chimeric orthopoxvirus encoding luciferase, enabling real-time view of cell infection), was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in triple-negative breast cancer (TNBC, an aggressive subtype of breast cancer with high recurrence rate and poor prognosis) lines with PI3K/AKT pathway mutations (47). Jung et al constructed two mathematical models to analyze the spread and expression of oncolytic measles viruses administered by direct intratumoral injection in vivo (42).…”

“…Thus, blindly increasing the application concentration of the virus to compensate for its lack of selectivity will inevitably increase the public concern about the safety of oncolytic virotherapy. Requires highly selective tissue targets (55) Absorbed slower than intravenous injection (65) Limited to central nervous system tumors (68) Applied only to small animals in which veins are difficult to find (65) Complex procedures make repeat dosing difficult (61,63) Physiological barriers such as blood-brain barrier and oncolytic virus elimination by the immune system (55) Mostly applied in vitro experiments (39,42,(44)(45)(46)(47) This route of administration, if any, would be the most likely to lead to toxicity (65) Additionally, those considering use of intravenous administration of an oncolytic virus also need to consider the existence of physiological barriers, such as blood-brain barrier, and the elimination of oncolytic virus by the immune system (55). Is it possible that a wide variety of oncolytic viruses can bypass the blood-brain barrier?…”

Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

“…Treatment-resistance to OVs is less likely because they mount an antitumor response through multiple pathways. Also, the interesting pharmacokinetics of OVs allows intracellular OV dose to increase over time from viral replication while drug concentrations traditionally decrease over time in other treatments [ 51 , 52 ]. These favorable findings have cemented researchers’ interest in oncolytic viruses.…”

Oncolytic virotherapy -in vivo veritas

“…In order to address this problem, we recently tested the hypothesis that measles virus mediated NIS expression and isotope uptake in tumors can be used to monitor the virus population in vivo . Intrinsic to this hypothesis is the assumption that isotope uptake would be proportional to the viable virus present in the tumor at that specific time [ 8 ]. In principle, the hypothesis is simple (Figure 1 ): infected cells express NIS and concentrate isotope that can be quantitatively measured using microSPECT/CT imaging.…”