TY - JOUR
T1 - Mesenchymal Stromal Cells for Linked Delivery of Oncolytic and Apoptotic Adenoviruses to Non-small-cell Lung Cancers
AU - Hoyos, Valentina
AU - Del Bufalo, Francesca
AU - Yagyu, Shigeki
AU - Ando, Miki
AU - Dotti, Gianpietro
AU - Suzuki, Masataka
AU - Bouchier-Hayes, Lisa
AU - Alemany, Ramon
AU - Brenner, Malcolm
N1 - Funding Information:
The authors thank Catherine Gillespie for the editing of the paper and Jeffrey Howard for his help in the set up of immunofluorescent stainings. This work was supported by the Cancer Prevention Research Institute of Texas (RP110553 P1 to M.K.B.) and the National Institutes of Health (R00HL098692 to M.S.).
Publisher Copyright:
© The American Society of Gene & Cell Therapy.
PY - 2015/9/3
Y1 - 2015/9/3
N2 - Oncolytic adenoviruses (OAdV) represent a promising strategy for cancer therapy. Despite their activity in preclinical models, to date the clinical efficacy remains confined to minor responses after intratumor injection. To overcome these limitations, we developed an alternative approach using the combination of the OAdv ICOVIR15 with a replication incompetent adenoviral vector carrying the suicide gene of inducible Caspase 9 (Ad.iC9), both of which are delivered by mesenchymal stromal cells (MSCs). We hypothesized that coinfection with ICOVIR15 and Ad.iC9 would allow MSCs to replicate both vectors and deliver two distinct types of antitumor therapy to the tumor, amplifying the cytotoxic effects of the two viruses, in a non-small-cell lung cancer (NSCLC) model. We showed that MSCs can replicate and release both vectors, enabling significant transduction of the iC9 gene in tumor cells. In the in vivo model using human NSCLC xenografts, MSCs homed to lung tumors where they released both viruses. The activation of iC9 by the chemical inducer of dimerization (CID) significantly enhanced the antitumor activity of the ICOVIR15, increasing the tumor control and translating into improved overall survival of tumor-bearing mice. These data support the use of this innovative approach for the treatment of NSCLC.
AB - Oncolytic adenoviruses (OAdV) represent a promising strategy for cancer therapy. Despite their activity in preclinical models, to date the clinical efficacy remains confined to minor responses after intratumor injection. To overcome these limitations, we developed an alternative approach using the combination of the OAdv ICOVIR15 with a replication incompetent adenoviral vector carrying the suicide gene of inducible Caspase 9 (Ad.iC9), both of which are delivered by mesenchymal stromal cells (MSCs). We hypothesized that coinfection with ICOVIR15 and Ad.iC9 would allow MSCs to replicate both vectors and deliver two distinct types of antitumor therapy to the tumor, amplifying the cytotoxic effects of the two viruses, in a non-small-cell lung cancer (NSCLC) model. We showed that MSCs can replicate and release both vectors, enabling significant transduction of the iC9 gene in tumor cells. In the in vivo model using human NSCLC xenografts, MSCs homed to lung tumors where they released both viruses. The activation of iC9 by the chemical inducer of dimerization (CID) significantly enhanced the antitumor activity of the ICOVIR15, increasing the tumor control and translating into improved overall survival of tumor-bearing mice. These data support the use of this innovative approach for the treatment of NSCLC.
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U2 - 10.1038/mt.2015.110
DO - 10.1038/mt.2015.110
M3 - Article
C2 - 26084970
AN - SCOPUS:84940671591
VL - 23
SP - 1497
EP - 1506
JO - Molecular therapy : the journal of the American Society of Gene Therapy
JF - Molecular therapy : the journal of the American Society of Gene Therapy
SN - 1525-0016
IS - 9
ER -