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. 2010 Oct;9(10):2761-9.
doi: 10.1158/1535-7163.MCT-10-0090. Epub 2010 Sep 21.

Genetically Engineered Oncolytic Newcastle Disease Virus Effectively Induces Sustained Remission of Malignant Pleural Mesothelioma

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Genetically Engineered Oncolytic Newcastle Disease Virus Effectively Induces Sustained Remission of Malignant Pleural Mesothelioma

Gerd R Silberhumer et al. Mol Cancer Ther. .
Free PMC article

Abstract

Malignant pleural mesothelioma is a highly aggressive tumor. Alternative treatment strategies such as oncolytic viral therapy may offer promising treatment options in the future. In this study, the oncolytic efficacy and induction of tumor remission by a genetically engineered Newcastle disease virus [NDV; NDV(F3aa)-GFP; GFP, green fluorescent protein] in malignant pleural mesothelioma is tested and monitored by bioluminescent tumor imaging. The efficacy of NDV(F3aa)-GFP was tested against several mesothelioma cell lines in vitro. Firefly luciferase-transduced MSTO-211H* orthotopic pleural mesothelioma tumor-bearing animals were treated with either single or multiple doses of NDV(F3aa)-GFP at different time points (days 1 and 10) after tumor implantation. Tumor burden was assessed by bioluminescence imaging. Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H > MSTO-211H* > H-2452 > VAMT > JMN. In vivo studies with MSTO-211H* cells showed complete response to viral therapy in 65% of the animals within 14 days after treatment initiation. Long-term survival in all of these animals was >50 days after tumor installation (control animals, <23 d). Multiple treatment compared with single treatment showed a significantly better response (P = 0.005). NDV seems to be an efficient viral oncolytic agent in the therapy of malignant pleural mesothelioma in an orthotopic pleural mesothelioma tumor model.

Figures

Figure 1
Figure 1. Cytotoxicity of NDV(F3aa)GFP against mesothelioma cell lines in vitro
LDH assays of mesothelioma cell lines of (a) JMN, (b) H-2452, (c) VAMT, and transduced (d) MSTO-211H* at different MOIs (0.01=dashed line, 0.1=dotted line, 1=solid line) at day 1, 3, 5, 7. Data are expressed as the ratio of surviving cells determined by comparing the LDH-concentration of infected sample relative to control untreated cells.
Figure 2
Figure 2. Overall survival of animals stratified by treatment groups
All control animals (control; solid line) were sacrificed due to tumor burden within 24 days , while the majority of treated animals exhibited survival to at least 90 days after tumor instillation. Animals receiving either single (T1S) or multiple (T1M) early treatment (Day 1) showed a 60% survival after 115 days. Animals out of the late treatment group (Day 10) showed 40% survival receiving multiple treatments (T10M) or had to be sacrificed within 95 days receiving single treatment (T10S).
Figure 3
Figure 3. Representative bioluminescence images demonstrate treatment effect of NDV(F3aa)GFP over time
Images were received 10 min after intraabdominal Luciferin injection with an acquisition time of 1sec. The control animals demonstrate an increasing bioluminescent signal after tumor instillation and had to be sacrificed due to tumor burden at the latest by day 24. Bioluminescent images of a representative animal of the control group are shown in Figure 3A. Animals receiving a single treatment on day 1 showed significant decrease of tumor signal within ten days after treatment. In Figure 3B a representative animal shows complete tumor signal elimination until day 13 after treatment start. Comparable results were investigated in animals receiving multiple treatments starting 10 days after tumor instillation (Figure 3C).
Figure 4
Figure 4. Values of thoracic bioluminescence signal decrease in all treatment groups
Each graph represents a single animal. Graphs labeled with * represent animals with no bioluminescent sign of tumor 14 days after treatment initiation. Graphs labeled with T represent animals with persistent tumor burden 14 days after treatment start. Bioluminescent values (p/s/cm2/sr) were calculated as following: (prone + spine value)/2. In the upper row animals are shown who received treatment starting one day after tumor injection. In the lower row animals are presented with treatment start on day 10 after tumor injection. A and C show animals who received single treatment, B and D represent animals with multiple treatments. The mean bioluminescent signal values decreased significantly more in animals receiving multiple treatments (day 1: p <0.01; day 10: p <0.01).

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