Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide - PubMed (original) (raw)

doi: 10.1038/sj.clpt.6100409. Epub 2007 Oct 31.

S M Greiner, M E Harvey, G Griesmann, M J Kuffel, S A Buhrow, J M Reid, M Federspiel, M M Ames, D Dingli, K Schweikart, A Welch, A Dispenzieri, K-W Peng, S J Russell

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Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide

R M Myers et al. Clin Pharmacol Ther. 2007 Dec.

Abstract

MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS). Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 x 10(6) TCID50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10(8) and 4 x 10(8) TCID50/kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1-2 x 10(4) TCID50/kg (10(6) TCID50 per patient).

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declared no conflict of interest.

Figures

Figure 1

Figure 1

Schematic illustration of the derivation of the infectious molecular clone (MV-Tag) that was used to generate recombinant MV-NIS by reverse genetics. The numbers indicate the number of passages in each of the indicated cellular substrate. (Adapted from ref. 2.)

Figure 2

Figure 2

Schematic representations of the MVs rescued from the plasmid molecular clones used to derive MV-NIS: p(+)MV-tag produced MVtag; p(+)MHlrGFPV produced MHlrGFPV; and p(+)MH-NIS(HP)3 produced the drug substance MV-NIS. To construct p(+)MH-NIS(HP)3, the _Mlu_I–_Aat_II fragment of p(+)MHlrGFPV containing the additional gene encoding rGFP was replaced with a PCR product containing the human NIS gene flanked by _Mlu_I and _Aat_II sites. An artificial gene boundary region (nucleotide sequence shown) was inserted into the _Spe_I site (position 9234) using two synthesized oligonucleotides. The p(+)MHlrGFPV plasmid was constructed by inserting the rGFP coding region into the _Mlu_I and _Nru_I cloning sites of the polylinker. The _Aat_II site is in the rGFP 3′-non-coding sequence. The p(+)MH-NIS(HP)3 plasmid was constructed by inserting the human NIS coding region into the _Mlu_I and _Aat_II sites of p(+)MHlrGFPV, replacing the rGFP gene. The position of the gene coding regions is indicated above the MVtag genome. To facilitate the comparison of the MV-NIS genome sequence (17,940 nucleotides) with other MV genomes of the Edmonston lineage (15,894 nucleotides), the 2,046 bp inserted transcription unit containing the NIS coding region is numbered separately (1N–2046N).

Figure 3

Figure 3

Schema for phase I clinical trial to assess the safety, maximum tolerated dose, and preliminary efficacy of MV-NIS administered intravenously with and without cyclophosphamide in patients with relapsed or refractory multiple myeloma. Correlative studies performed are summarized in the table of this figure.

Figure 4

Figure 4

Survival and individual tumor volume in SCID mice bearing subcutaneous KAS-6/1 multiple myeloma xenografts treated with various doses of MV-NIS. (a) Survival proportions (UV-inactivated, black; 104 TCID50, red; 105 TCID50, blue; 106 TCID50, green; 107 TCID50, purple). Individual tumor volumes plotted for mice treated with (b) UV-inactivated, (c) 104 TCID50, (d) 105 TCID50, (e) 106 TCID50, and (f) 107 TCID50 MV-NIS.

Figure 5

Figure 5

Biodistribution of MV-NIS genome in IfnarKO × CD46 Ge mice after intravenous administration of 107 TCID50 MV-NIS day 0 with and without 125 mg/kg cyclophosphamide (CP) pretreatment day −1. (a) Day 2, (b) day 5, (c) day 22, (d) day 91. Data normalized per microgram of total RNA. Closed diamonds, without CP; open diamonds, with CP; black, brain; red, lung; blue, liver; orange, kidney; green, spleen; purple, blood; and brown, gonads. Limit of detection (LOD) of QRT-PCR assay is 100 copies of MV nucleoprotein RNA per microgram of total RNA.

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