Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

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 × 10 6 TCID 50 (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 × 10 8 TCID 50 /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 × 10 4 TCID 50 /kg (10 6 TCID 50 per patient).Measles virus (MV, family Paramyxoviridae) was isolated in 1954 from the throat washings of a measles patient, David Edmonston. 1 Tissue culture passage resulted in loss of pathogenicity and attenuation of wild-type MV (Figure 1), giving rise to the Edmonston measles vaccines used worldwide today. 2 We recently discovered that attenuated Edmonston strain MV has potent antitumor activity in vitro and in vivo. 3 Intravenous, intratumoral, or intraperitoneal administration of the virus inhibited tumor growth or induced tumor regression in a variety of human tumor xenograft models. [4][5][6][7] To tailor the virus for cancer therapy, we Correspondence: SJ Russell (sjr@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2009 October 28. Published in final edited form as:Clin Pharmacol Ther. 2007 December ; 82(6): 700-710. doi:10.1038/sj.clpt.6100409. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripthave genetically engineered the viral coat protein to display tumor-targeting ligands to enable tumor-specific killing or inserted trackable transgenes into the viral genome to enable noninvasive monitoring of viral gene expression. [8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue. Expression of NIS allows cells to actively transport iodide ions into the cell. Thus, patients with thyroid cancer are typically treated with 131 I to destroy the NIS-expressing thyroid cancer while leaving most normal tissues undamaged. 13 Loss of thyroid function due to the radiotherapy can be treated by replacement therapy with synthetic thyroid hormones. Insertion of NIS into MV facilitates pharmacokinetic evaluation and enhancement of MV oncolytic activity. MV-NIS-infected cells express...

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“…Measles virus (47,48) was used against ovarian cancer and myeloma in preclinical studies that preceded an ongoing phase I trial where virally expressed hNIS is used for imaging the viral propagation. Vesicular stomatitis virus has been coupled to 131 I therapy with promising results (40).…”

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Le virus de la rougeole

“…Dans un modèle murin d'adéno-carcinome colique, l'association de cyclophosphamide au virus de la rougeole armé d'un gène suicide a permis de retarder l'apparition d'anticorps neutralisant le virus et d'augmenter la réponse antitumorale jusqu'à obtenir 90 % de réponse complète [15]. Une stratégie combinant virus de la rougeole et cyclophosphamide a été évaluée dans une étude préclinique du traitement du myélome [28] et un essai clinique de phase 1 est en cours à la Mayo Clinic. Cependant, un cas d'encéphalite aiguë à inclusions a été décrit chez un enfant immunodéprimé ayant reçu une dose vaccinale de virus modification de ce modèle a été créée : une séquence de type interleukine 13 a été introduite à l'extrémité carboxy-terminale de la protéine H ; comme les cellules de glioblastome surexpriment le récepteur à l'interleukine 13, le virus se liera de façon préférentielle aux cellules tumorales.…”