Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus.
Oncolytic viruses that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. However, the oncolytic potency of replicating agents is determined directly by their capability of infecting target cells. Most adenoviruses used for gene therapy or virotherapy have been based on serotype 5 (Ad5). Unfortunately, expression of the primary receptor for Ad5 (the coxsackie-adenovirus receptor, or CAR) is highly variable on ovarian and other cancer cells. By performing genetic fiber pseudotyping, we created Ad5/3-Delta24, a conditionally replicating adenovirus that does not bind CAR but facilitates entry into and killing of ovarian cancer cells. We show replication of Ad5/3-Delta24 and subsequent oncolysis of ovarian adenocarcinoma lines. Replication was also analyzed with quantitative PCR on three-dimensional primary tumor cell spheroids purified from patient samples. Moreover, in a therapeutic orthotopic model of peritoneal carcinomatosis, dramatically enhanced survival was noted. Finally, Ad5/3-Delta24 achieved a significant antitumor effect as assessed by noninvasive, in vivo bioluminescence imaging. Therefore, the preclinical therapeutic efficacy of Ad5/3-Delta24 is improved over the respective CAR- and integrin-binding controls. Taken together with promising biodistribution and toxicity data, this approach could translate into successful clinical interventions for ovarian cancer patients.
Kanerva
Anna
A
Division of Human Gene Therapy, Department of Medicine, Department of Pathology, and Department of Surgery, Finland.
Zinn
Kurt R
KR
Chaudhuri
Tandra R
TR
Lam
John T
JT
Suzuki
Kaori
K
Uil
Taco G
TG
Hakkarainen
Tanja
T
Bauerschmitz
Gerd J
GJ
Wang
Minghui
M
Liu
Bin
B
Cao
Zhihong
Z
Alvarez
Ronald D
RD
Curiel
David T
DT
Hemminki
Akseli
A
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D005260:Female; D008163:Luminescent Measurements; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013997:Time Factors
D011956:Receptors, Cell Surface