Combined transductional untargeting/retargeting and transcriptional restriction enhances adenovirus gene targeting and therapy for hepatic colorectal cancer tumors.
Unresectable hepatic colorectal cancer (CRC) metastases are a leading cause of cancer mortality. These tumors and other epithelial tumors often express both cyclooxygenase-2 (COX-2) and carcinoembryonic antigen (CEA). Because adenovirus (Ad) vectors infect the liver and lack tumor tropism, they cannot be used for systemic therapy of hepatic metastases. We used COX-2 transcriptional restriction, in combination with transductional Ad hepatic untargeting and tumor retargeting by a bispecific adapter, sCARhMFE, composed of sCAR [the coxsackie/Ad receptor (CAR) ectodomain] and MFE-23 (a single-chain anti-CEA antibody), to untarget liver after i.v. administration of Ad vectors expressing firefly luciferase and to retarget virus to hepatic colorectal tumor xenografts and non-small cell lung tumor xenografts. To improve both liver untargeting and tumor retargeting, we developed sCARfMFE, a trimerized sCARhMFE adapter. Trimerization greatly improves both untargeting of CAR-dependent Ad infection and CEA-dependent virus retargeting in culture and in vivo. Combining sCARfMFE bispecific adapter transductional liver untargeting and transductional tumor retargeting with COX-2 transcriptional tumor-restricted transgene expression increases systemically administered Ad therapeutic efficacy for hepatic CRC tumors, using herpes virus type 1 thymidine kinase (HSV1-tk) as a therapeutic gene in conjunction with the prodrug ganciclovir (GCV). Both transductional untargeting and COX-2 transcriptional restriction also reduce HSV1-tk/GCV hepatic toxicity. In addition, transductional sCARfMFE untargeting reduces the innate immune response to systemic Ad administration. Combined transductional liver Ad untargeting, transductional tumor retargeting, and transcriptional transgene restriction suggests a means to engineer practical, effective therapeutic agents for hepatic CRC metastases in particular, as well as hepatic metastases of other epithelial cancers.
Li
Hua-Jung
HJ
Departments of Biological, Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90095, USA.
Everts
Maaike
M
Yamamoto
Masato
M
Curiel
David T
DT
Herschman
Harvey R
HR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D051546:Cyclooxygenase 2 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D002272:Carcinoembryonic Antigen; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007128:Immunoglobulin Fragments; C451184:MFE-23 protein, human; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D051546:Cyclooxygenase 2