TY - JOUR
T1 - Defining a murine ovarian cancer model for the evaluation of conditionally-replicative adenovirus (CRAd) virotherapy agents
AU - González-Pastor, Rebeca
AU - Ashshi, Ahmad Mohammad
AU - El-Shemi, Adel Galal
AU - Dmitriev, Igor P.
AU - Kashentseva, Elena A.
AU - Lu, Zhi Hong
AU - Goedegebuure, S. Peter
AU - Podhajcer, Osvaldo L.
AU - Curiel, David T.
N1 - Funding Information:
The authors wish to acknowledge the help of William Hawkins for input and advice in the design of these studies. We also wish to acknowledge the generous support of the Department of Obstetrics and Gynecology. The authors gratefully acknowledge use of the services and facilities of the Molecular Imaging Center (funded by NIH P50 CA094056) and the Siteman Cancer Center Small Animal Cancer Imaging shared resource (funded by NCI P30 CA091842).
Funding Information:
This study was funded by the Research Grants, King Abdul Aziz City for Science and Technology (KACST) the Kingdom of Saudi Arabia Award Number (ARP-35-104). Dr. Ashshi and Dr. El-Shemi are the recipients of the grant. Also by the Department of Defense Ovarian Cancer Research Program (W81XWH-18-1-0063).
Publisher Copyright:
© 2019 The Author(s).
PY - 2019/2/15
Y1 - 2019/2/15
N2 - Background: Virotherapy represents a promising approach for ovarian cancer. In this regard, conditionally replicative adenovirus (CRAd) has been translated to the context of human clinical trials. Advanced design of CRAds has sought to exploit their capacity to induce anti-tumor immunization by configuring immunoregulatory molecule within the CRAd genome. Unfortunately, employed murine xenograft models do not allow full analysis of the immunologic activity linked to CRAd replication. Results: We developed CRAds based on the Ad5/3-Delta24 design encoding cytokines. Whereas the encoded cytokines did not impact adversely CRAd-induced oncolysis in vitro, no gain in anti-tumor activity was noted in immune-incompetent murine models with human ovarian cancer xenografts. On this basis, we explored the potential utility of the murine syngeneic immunocompetent ID8 ovarian cancer model. Of note, the ID8 murine ovarian cancer cell lines exhibited CRAd-mediated cytolysis. The use of this model now enables the rational design of oncolytic agents to achieve anti-tumor immunotherapy. Conclusions: Limits of widely employed murine xenograft models of ovarian cancer limit their utility for design and study of armed CRAd virotherapy agents. The ID8 model exhibited CRAd-induced oncolysis. This feature predicate its potential utility for the study of CRAd-based virotherapy agents.
AB - Background: Virotherapy represents a promising approach for ovarian cancer. In this regard, conditionally replicative adenovirus (CRAd) has been translated to the context of human clinical trials. Advanced design of CRAds has sought to exploit their capacity to induce anti-tumor immunization by configuring immunoregulatory molecule within the CRAd genome. Unfortunately, employed murine xenograft models do not allow full analysis of the immunologic activity linked to CRAd replication. Results: We developed CRAds based on the Ad5/3-Delta24 design encoding cytokines. Whereas the encoded cytokines did not impact adversely CRAd-induced oncolysis in vitro, no gain in anti-tumor activity was noted in immune-incompetent murine models with human ovarian cancer xenografts. On this basis, we explored the potential utility of the murine syngeneic immunocompetent ID8 ovarian cancer model. Of note, the ID8 murine ovarian cancer cell lines exhibited CRAd-mediated cytolysis. The use of this model now enables the rational design of oncolytic agents to achieve anti-tumor immunotherapy. Conclusions: Limits of widely employed murine xenograft models of ovarian cancer limit their utility for design and study of armed CRAd virotherapy agents. The ID8 model exhibited CRAd-induced oncolysis. This feature predicate its potential utility for the study of CRAd-based virotherapy agents.
KW - Adenovirus
KW - Anti-tumor immunization
KW - CRAd
KW - ID8
KW - Ovarian cancer
KW - Virotherapy
UR - http://www.scopus.com/inward/record.url?scp=85061619810&partnerID=8YFLogxK
U2 - 10.1186/s13048-019-0493-5
DO - 10.1186/s13048-019-0493-5
M3 - Article
C2 - 30767772
AN - SCOPUS:85061619810
SN - 1757-2215
VL - 12
JO - Journal of ovarian research
JF - Journal of ovarian research
IS - 1
M1 - 18
ER -