Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors.
Systemic adenoviral delivery into tumors is inefficient because of liver sequestration of intravenously administered virus. One potential solution for improving bioavailability is the use of carrier cells such as human mesenchymal stem cells (MSCs), which have been suggested to have inherent tumor tropism. Here we investigated the capacity of capsid-modified adenoviruses to infect and replicate in MSCs. Further, biodistribution and tumor-killing efficacy of MSCs loaded with oncolytic adenoviruses were evaluated in orthotopic murine models of lung and breast cancer. In vitro, heparan sulfate proteoglycan- and alpha(v)beta integrin-targeted viruses enhanced gene delivery to bone marrow- and adipose tissue-derived MSCs up to 11,000-fold over adenovirus serotype 5 (Ad5). Infectivity-enhanced oncolytic adenoviruses showed notably higher rates of cytolysis of in vitro-passaged MSCs in comparison with wild-type virus. In vivo, intravenously injected MSCs homed primarily to the lungs, and virus was released into advanced orthotopic breast and lung tumors for therapeutic efficacy and increased survival. When the same dose of virus was injected intravenously without MSCs, only transduction of the liver was seen. These results suggest that MSCs loaded with oncolytic adenoviruses might be a useful approach for improving the bioavailability of systemically administered oncolytic adenoviruses.
Hakkarainen
Tanja
T
Cancer Gene Therapy Group, Molecular Cancer Biology Program and Haartman Institute, University of Helsinki, 00014 Helsinki, Finland.
Särkioja
Merja
M
Lehenkari
Petri
P
Miettinen
Susanna
S
Ylikomi
Timo
T
Suuronen
Riitta
R
Desmond
Renee A
RA
Kanerva
Anna
A
Hemminki
Akseli
A
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D014161:Transduction, Genetic; D018523:Tropism; D014779:Virus Replication