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. 2011 Jun;19(6):1041-7.
doi: 10.1038/mt.2011.68. Epub 2011 Apr 19.

Myeloma xenograft destruction by a nonviral vector delivering oncolytic infectious nucleic acid

Elizabeth M Hadac  1 , Elizabeth J Kelly, Stephen J Russell
Affiliations

Myeloma xenograft destruction by a nonviral vector delivering oncolytic infectious nucleic acid

Elizabeth M Hadac et al. Mol Ther. 2011 Jun.

Abstract

The feasibility of using a nonviral vector formulation to initiate an oncolytic viral infection has not been previously demonstrated. We therefore sought to determine whether infectious nucleic acid (INA) could be used in place of virus particles to initiate an oncolytic picornavirus infection in vivo. Infectious RNA encoding coxsackievirus A21 (CVA21) was transcribed from plasmid DNA using T7 polymerase. Within 48 hours of injecting this RNA into KAS6/1 myeloma xenografts, high titers of infectious CVA21 virions were detected in the bloodstream. Tumors regressed rapidly thereafter and mice developed signs of myositis. At euthanasia, CVA21 was recovered from regressing tumors and from skeletal muscles. Treatment outcomes were comparable following intratumoral injection of naked RNA or fully infectious CVA21 virus. Dose-response studies showed that an effective oncolytic infection could be established by intratumoral injection of 1 µg of infectious RNA. The oncolytic infection could also be initiated by intravenous injection of infectious RNA. Our study demonstrates that INA is a highly promising alternative drug formulation for oncolytic virotherapy.

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Figures

Figure 1
Figure 1
Characterization of coxsackievirus A21 (CVA21) RNA by electrophoresis and assessment of viral production. (a) RNA Flash Gel with molecular weight (kb) markers (left) and CVA21 transcript (right). (b) Time-course of virus production in H1-HeLa cells transfected with CVA21 RNA. TCID50, tissue culture infectious dose 50.
Figure 2
Figure 2
In vivo demonstration of tumor response to intratumorally injected coxsackievirus A21 (CVA21) RNA. Tumor volumes of SCID mice carrying subcutaneous Kas6/1 human myeloma xenografts were treated with (a) 106 TCID50 CVA21 virus (n = 3), (b) Opti-MEM control (n = 8), (c) 20 µg CVA21 RNA (n = 7) or (d) 20 µg CVA21 RNA treated with 60 µg RNaseA (n = 2). Based on the segmented model, there was no overall group effect (P = 0.16) or group effect prior to day 6 (P = 0.49). There was, however, a significant effect after day 6 (P < 0.0001) with reductions of tumor volume in the RNA (P < 0.0001) and virus (P < 0.0001) groups compared to the control group. There was no after day 6 difference in the RNA + Rnase group compared to the control group (P = 0.29). MEM, minimal essential medium.
Figure 3
Figure 3
Formalin-fixed paraffin-embedded tumor sections stained by hematoxylin and eosin. Microscopic images shows inflammation and necrosis in (a) coxsackievirus A21 (CVA21) virus and (b) CVA21 RNA treated tumors while the (c) Opti-MEM control and (d) CVA21RNA + RNaseA tumors are within normal limits. Bar = 0.1 mm. MEM, minimal essential medium.
Figure 4
Figure 4
In vivo dose–response of tumor regression following intratumoral treatment with coxsackievirus A21 (CVA21) RNA. Tumor volumes of SCID mice carrying subcutaneous Kas6/1 human myeloma xenografts were treated with (a) Opti-MEM control, (b) 1 µg, (c) 2 µg, (d) 4 µg, (e) 8 µg, (f) 16 µg, or (g) 32 µg CVA21 RNA. Mice with tumor progression (gray lines), mice with tumor regression (black lines). (h) Kaplan–Meier survival curves of control and RNA treated mice. Based on the segmented model, there was no overall dose effect (P = 0.19) or dose effect prior to day 10 (P = 0.20). There was, however, a significant dose effect after day 10 (P = 0.0008) showing increased dose was associated with decrease in tumor volume. This was confirmed when evaluating the after day 10 results in a separate model (P < 0.0001). MEM, minimal essential medium.
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