Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy.
We have developed an approach to cancer gene therapy in which the oncolytic effects of an adenoviral vector have been combined with selective expression of a soluble form of transforming growth factor (TGF)-beta receptor II fused with Fc (sTGFbetaRIIFc). We chose to use adenoviral dl01/07 mutant because it can replicate in all cancer cells regardless of their genetic defects. An oncolytic adenovirus expressing sTGFbetaRIIFc (Ad.sT- betaRFc) was constructed by homologous recombination. Infection of MDA-MB-231 and MCF-7 human breast cancer cells with Ad.sTbetaRFc produced sTGFbetaRIIFc, which was released into the media. The conditioned media containing sTGFbetaRIIFc could bind with TGF-beta 1 and inhibited TGF-beta-dependent transcription in target cells. Infection of MDA-MB-231, MCF-7, and 76NE human breast cancer cells with Ad.sTbetaRFc resulted in high levels of viral replication, comparable to that of a wild-type dl309 virus. Although some viral replication was observed in actively dividing normal human lung fibroblasts, there was no replication in nonproliferating normal cells. Direct injection of Ad.sTbetaRFc into MDA-MB-231 human breast xenograft tumors grown in nude mice resulted in a significant inhibition of tumor growth, causing tumor regression in more than 85% of the animals. These results indicate that it is possible to construct an oncolytic virus expressing sTGFbetaRIIFc in which both viral replication and transgene expression remain intact, and the recombinant adenovirus is oncolytic in a human tumor xenograft model. On the basis of these results we believe that it may be feasible to develop a cancer gene therapy approach using Ad.sTbetaRFc as an antitumor agent.
Seth
Prem
P
Gene Therapy Program, Evanston Northwestern Healthcare Research Institute and Department of Medicine, Evanston Hospital, Northwestern University, Evanston, IL 60201, USA. pseth@northwestern.edu
Wang
Zhen-Guo
ZG
Pister
Amanda
A
Zafar
M Behzad
MB
Kim
Sung
S
Guise
Theresa
T
Wakefield
Lalage
L
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D015398:Signal Transduction; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D007141:Immunoglobulin Fc Fragments; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II