Robust Oncolytic Virotherapy Induces Tumor Lysis Syndrome and Associated Toxicities in the MPC-11 Plasmacytoma Model.
Tumor-selective oncolytic vesicular stomatitis viruses (VSVs) are being evaluated in clinical trials. Here, we report that the MPC-11 murine plasmacytoma model is so extraordinarily susceptible to oncolytic VSVs that a low dose of virus leads to extensive intratumoral viral replication, sustained viremia, intravascular coagulation, and a rapidly fatal tumor lysis syndrome (TLS). Rapid softening, shrinkage and hemorrhagic necrosis of flank tumors was noted within 1-2 days after virus administration, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, increase in plasma cell free DNA, lymphopenia, consumptive coagulopathy, increase in fibrinogen degradation products, decreased liver function tests, dehydration, weight loss, and euthanasia or death after 5-8 days. Secondary viremia was observed but viral replication in normal host tissues was not detected. Toxicity could be mitigated by using VSVs with slowed replication kinetics, and was less marked in animals with smaller flank tumors. The MPC-11 tumor represents an interesting model to further study the complex interplay of robust intratumoral viral replication, tumor lysis, and associated toxicities in cases where tumors are highly responsive to oncolytic virotherapy.
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Lianwen
L
Zhang
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Michael B
MB
Steele
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Nathan
N
Jenks
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Jacquelyn
J
Grell
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Marshall
M
Behrens
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Rebecca
R
Nace
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Shruthi
S
Naik
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Viral Vector Production Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Mark J
MJ
Federspiel
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Stephen J
SJ
Russell
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Kah-Whye
KW
Peng
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy / Q000009:adverse effects*; D050504:Oncolytic Viruses / Q000235:genetics; D010954:Plasmacytoma / Q000628:therapy*; D016896:Treatment Outcome; D015275:Tumor Lysis Syndrome / Q000209:etiology*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics*
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