Antiangiogenic arming of an oncolytic vaccinia virus enhances antitumor efficacy in renal cell cancer models.
Oncolytic vaccinia viruses have shown compelling results in preclinical cancer models and promising preliminary safety and antitumor activity in early clinical trials. However, to facilitate systemic application it would be useful to improve tumor targeting and antitumor efficacy further. Here we report the generation of vvdd-VEGFR-1-Ig, a targeted and armed oncolytic vaccinia virus. Tumor targeting was achieved by deletion of genes for thymidine kinase and vaccinia virus growth factor, which are necessary for replication in normal but not in cancer cells. Given the high vascularization typical of kidney cancers, we armed the virus with the soluble vascular endothelial growth factor (VEGF) receptor 1 protein for an antiangiogenic effect. Systemic application of high doses of vvdd-VEGFR-1-Ig resulted in cytokine induction in an immunocompromised mouse model. Upon histopathological analysis, splenic extramedullary hematopoiesis was seen in all virus-injected mice and was more pronounced in the vvdd-VEGFR-1-Ig group. Analysis of the innate immune response after intravenous virus injection revealed high transient and dose-dependent cytokine elevations. When medium and low doses were used for intratumoral or intravenous injection, vvdd-VEGFR-1-Ig exhibited a stronger antitumor effect than the unarmed control. Furthermore, expression of VEGFR-1-Ig was confirmed, and a concurrent antiangiogenic effect was seen. In an immunocompetent model, systemic vvdd-VEGFR-1-Ig exhibited superior antitumor efficacy compared to the unarmed control virus. In conclusion, the targeted and armed vvdd-VEGFR-1-Ig has promising anticancer activity in renal cell cancer models. Extramedullary hematopoiesis may be a sensitive indicator of vaccinia virus effects in mice.
Guse
Kilian
K
Cancer Gene Therapy Group, Biomedicum Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.
Sloniecka
Marta
M
Diaconu
Iulia
I
Ottolino-Perry
Kathryn
K
Tang
Nan
N
Ng
Calvin
C
Le Boeuf
Fabrice
F
Bell
John C
JC
McCart
J Andrea
JA
Ristimäki
Ari
A
Pesonen
Sari
S
Cerullo
Vincenzo
V
Hemminki
Akseli
A
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007121:Immunocompetence; D016867:Immunocompromised Host; D007668:Kidney / Q000166:cytology / Q000821:virology; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D013937:Thymidine Kinase; D040281:Vascular Endothelial Growth Factor Receptor-1