Preclinical pharmacology and toxicology of intravenous MV-NIS, an oncolytic measles virus administered with or without cyclophosphamide.
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).
Myers
R M
RM
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Greiner
S M
SM
Harvey
M E
ME
Griesmann
G
G
Kuffel
M J
MJ
Buhrow
S A
SA
Reid
J M
JM
Federspiel
M
M
Ames
M M
MM
Dingli
D
D
Schweikart
K
K
Welch
A
A
Dispenzieri
A
A
Peng
K-W
KW
Russell
S J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008459:Measles virus / Q000235:genetics / Q000302:isolation & purification; D051916:Membrane Cofactor Protein / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses; D012367:RNA, Viral / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012453:Saimiri; D027981:Symporters / Q000008:administration & dosage / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D000099209:Sodium-Iodide Symporters
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D051916:Membrane Cofactor Protein; D012367:RNA, Viral; D027981:Symporters; D000099209:Sodium-Iodide Symporters