CG0070, a conditionally replicating granulocyte macrophage colony-stimulating factor--armed oncolytic adenovirus for the treatment of bladder cancer.
OBJECTIVE
The purpose of this study was to examine the tumor specificity, cytotoxicity, and granulocyte macrophage colony-stimulating factor expression of CG0070, a conditionally replicating oncolytic adenovirus, in human bladder transitional cell carcinoma (TCC) cell lines and determine its antitumor efficacy in bladder TCC tumor models.


METHODS
Virus yield and cytotoxicity assays were used to determine tumor specificity and virus replication-mediated cytotoxicity of CG0070 in a panel of human bladder TCC cell lines and primary cells in vitro. Two s.c. and one orthotopic bladder TCC xenograft tumor models were used to assess antitumor activity of CG0070.


RESULTS
In a matched isogenic pair of cell lines with differing retinoblastoma (Rb) pathway status, CG0070 showed selective E1a and granulocyte macrophage colony-stimulating factor (GM-CSF) expression in Rb pathway-defective cells. CG0070 replicated in Rb-defective bladder TCC cell lines as efficiently as wild-type adenovirus but produced 100-fold less virus in normal human cells. CG0070 was up to 1,000-fold more cytotoxic in Rb pathway-defective bladder TCC cells in comparison with normal human cells. Antitumor activity of CG0070 was shown in two bladder TCC s.c. xenograft tumor models following intratumoral injections and intravesical treatment in an orthotopic xenograft tumor model when compared with PBS treatment.


CONCLUSIONS
In vitro and in vivo studies showed the selective replication, cytotoxicity, GM-CSF production, and antitumor efficacy of CG0070 in several bladder TCC models, suggesting a potential utility of this oncolytic agent for the treatment of bladder cancer. Further studies are warranted to show the role of human GM-CSF in the antitumor efficacy of CG0070.
Ramesh
Nagarajan
N
Cell Genesys, Inc., South San Francisco, California 94080, USA.
Ge
Ying
Y
Ennist
David L
DL
Zhu
Mingzhu
M
Mina
Mervat
M
Ganesh
Shanthi
S
Reddy
P Seshidhar
PS
Yu
De-Chao
DC
D000256:Adenoviridae / Q000235:genetics; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000628:therapy / Q000821:virology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000628:therapy / Q000821:virology*; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D000972:Antineoplastic Agents, Phytogenic; D016160:Retinoblastoma Protein; D043823:Taxoids; D000077143:Docetaxel; D016178:Granulocyte-Macrophage Colony-Stimulating Factor