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. 2012 Mar;19(3):202-11.
doi: 10.1038/cgt.2011.82. Epub 2011 Nov 25.

Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus

Y-P Liu  1 , C Tong, A Dispenzieri, M J Federspiel, S J Russell, K-W Peng
Affiliations

Polyinosinic acid decreases sequestration and improves systemic therapy of measles virus

Y-P Liu et al. Cancer Gene Ther. 2012 Mar.

Abstract

Off-target binding or vector sequestration can significantly limit the efficiency of systemic virotherapy. We report here that systemically administered oncolytic measles virus (MV) was rapidly sequestered by the mononuclear phagocytic system (MPS) of the liver and spleen in measles receptor CD46-positive and CD46-negative mice. Since scavenger receptors on Kupffer cells are responsible for the elimination of blood-borne pathogens, we investigated here if MV uptake was mediated by scavenger receptors on Kupffer cells. Pretreatment of cells with poly(I), a scavenger receptor ligand, reduced MV expression by 99% in murine (J774A.1) macrophages and by 50% in human (THP-1) macrophages. Pre-dosing of mice with poly(I) reduced MPS sequestration of MV and increased circulating levels of MV by 4 to 15-folds at 2 min post virus administration. Circulating virus was still detectable 30 min post infusion in mice pre-dosed with poly(I) whereas no detectable MV was found at 5-10 min post infusion if mice did not receive poly(I). MPS blockade by poly(I) enhanced virus delivery to human ovarian SKOV3ip.1 and myeloma KAS6/1 xenografts in mice. Higher gene expression and improved control of tumor growth was noted early post therapy. Based on these results, incorporation of MPS blockade into MV treatment regimens is warranted.

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Figures

Figure 1
Figure 1
Systemically administered MV viruses are sequestered from circulation in both CD46 negative athymic mice and CD46 positive Ifnar-CD46Ge mice. Clearance of MV viruses from circulation post intravenous injection of 106 TCID50 MV-Luc into (a) CD46 positive mice or (b) CD46 negative mice. The decay graphs between 0–10 min are magnified and shown on the right upper corner as inserts.
Figure 2
Figure 2
Systemically administered MV particles are sequestered by macrophages in the liver and spleen of CD46 negative athymic and CD46 positive Ifnar-CD46Ge mice. (a) Fluorescence microscopy shows the sequestration of green fluorescent DiO-MV particles in the liver and spleen after intravenous delivery. Control = no virus given. 50X magnification. (b) Representative confocal microscopy images of liver and spleen cryosections showing colocalization of red fluorescent DiI-MV particles with CD68 positive (Alexa-488/green color) macrophages. 400X magnification. (c) Quantitative RT-PCR data showing the biodistribution of MV genomes in the major organs of mice post intravenous delivery of 1.5×107 TCID50 MV-NIS. Results are expressed as mean ± SD (n=3 mice). *indicate that the two groups are statistically different (p<0.05).
Figure 3
Figure 3
Poly(I) reduces MV-Luc infection of macrophages in vitro. Relative luciferase gene-expression levels in human monocyte (THP-1), human macrophage (THP-1 treated with PMA), and murine macrophage (J774A.1) cell lines in the absence (MV-Luc only) or presence of poly(A) or poly(I) and MV-Luc. Gene expression is presented as a percentage of that in cells infected with MV-Luc in the absence of poly(I). Results are expressed as the mean ± SD of three different experiments. * indicate statistically different (p<0.05) against MV only group.
Figure 4
Figure 4
Poly(I) reduces uptake of MV particles by the liver and spleen, enhancing bioavailability of MV in the blood of mice. CD46-negative and CD46-positive mice were injected intravenously with PBS or 0.2 mg poly(I) per mouse 5 min prior to administration of 106 TCID50 DiI-MV-Luc. (a) Numbers of red fluorescent cells (due to uptake of DiI-MV) in liver and spleen cryosection were counted (pixels) using the Image J software. Data is presented as a percentage of that in mice given MV only. Blood from (b) CD46-negative or (c) CD46-positive mice were collected at 2, 5, 10 and 30 min after MV injection and analyzed for infectious virus by TCID50 assay. Results are expressed as mean ± SD (n=3 mice). *indicate statistically different (p<0.05) against no poly(I).
Figure 5
Figure 5
Poly(I) enhanced MV delivery to the tumor site and improved antitumor activity of MV at early time points post therapy. Mice with subcutaneous SKOV3ip.1 xenografts were injected intravenously with saline or poly(I), followed by a single dose of MV-Luc. Mice were imaged at day 5 and day 10 post MV on a Xenogen 200 machine. (a) Bioluminescent images showing higher MV-Luc gene expression in tumors of mice predosed with poly(I). (b) The luciferase activities in the tumors were quantitated and graphed. The efficacy of single dose MV-NIS therapy with or without poly(I) pre-dosing was evaluated by comparing tumor growth over time in (c) SKOV3ip.1 ovarian (N=10 mice per group) and (d) KAS 6/1 myeloma (N=8 mice per group) xenografts. Pretreatment of mice with poly(I) was associated with a significant retardation in tumor growth. *indicate statistically different (p<0.05) from saline group at the respective time point.
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References

    1. Chiocca EA. The host response to cancer virotherapy. Current opinion in molecular therapeutics. 2008;10(1):38–45. - PubMed
    1. Liu TC, Galanis E, Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nature clinical practice. 2007;4(2):101–17. - PubMed
    1. Melcher A, Parato K, Rooney CM, Bell JC. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol Ther. 2011;19(6):1008–16. - PMC - PubMed
    1. Park BH, Hwang T, Liu TC, Sze DY, Kim JS, Kwon HC, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. The lancet oncology. 2008;9(6):533–42. - PubMed
    1. Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27(34):5763–71. - PubMed

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