We hypothesize that a novel capsid incorporation approach will allow comprehensive in vivo monitoring of a cancer retargeted vector, and permit the assessment of our novel vector engineering strategy to enable targeted therapy of disseminated neoplastic disease. By investigating adenovirus (Ad) vector design, we anticipate the new information gained from this initiative will demonstrate the utility of our highly novel imaging approach, and validate the specificity of retargeted tumor transduction. The goal of this application is to develop a multi-functional Ad vector that combines both imaging and targeted therapy. To fulfill this goal, we will combine three unique technologies to advance therapeutic targeting of disseminated neoplastic disease: cancer-specific retargeting, liver-detargeting, and non-invasive imaging. We have developed Ad vectors capable of cell-specific targeting, by incorporating targeting single chain antibodies (scFv) into the viral capsid in combination with hexon modification for liver detargeting and evasion of pre-existing immunity. Our innovative Ad targeting approach provides a novel way to circumvent the problem of structural and biosynthetic incompatibility between Ad and complex targeting ligands such as scFv, and could facilitate Ad targeting to a wide variety of clinically important cell populations using novel targeting ligands including recombinant antibodies and growth factors The goal of this application is to develop a multi-functional Ad vector that combines both imaging and targeted therapy. To fulfill this goal, we will combine three unique technologies to advance therapeutic targeting of disseminated neoplastic disease: cancer-specific retargeting, liver-detargeting, and non-invasive imaging. We have developed Ad vectors capable of cell-specific targeting, by incorporating targeting single chain antibodies (scFv) into the viral capsid in combination with hexon modification for liver detargeting and evasion of pre-existing immunity. Our innovative Ad targeting approach provides a novel way to circumvent the problem of structural and biosynthetic incompatibility between Ad and complex targeting ligands such as scFv, and could facilitate Ad targeting to a wide variety of clinically important cell populations Our innovative use of a structural fusion protein incorporating metallothionein into adenovirus pIX gene provides the non-invasive imaging advantages of detecting physical biodistribution and spread of Ad vectors after administration that is not possible employing a reporter gene. Further, the ability to noninvasively observe Ad function on a whole-body level allows the possibility of detecting virus dissemination outside the tumor site(s) for monitoring clinical safety. By combining these modifications in Ad vector design, we anticipate the new information gained from this initiative will demonstrate the utility of our highly novel imaging approach, and validate the specificity of targeted tumor transduction. This work addresses the significant unmet need of new therapies for advanced stage metastatic cancer. The novel design of the proposed imaging approach is distinct from previously described vector imaging modalities, which have been based exclusively on monitoring the expression of reporter genes. In addition, our combined technologies have broad impact on the diverse field of gene therapy, in which the ability to achieve both cell- specific transduction and monitoring is universally required. To accomplish these goals, we have assembled an outstanding team of investigators with expertise in Ad vector design and construction, adenovirus retargeting approaches, preclinical models using Ad vectors, non-invasive PET and SPECT imaging, medical physics, colon cancer oncology and clinical trials, clinical pathology, biostatistics, and preclinical toxicology.

Public Health Relevance

The goal of this application is to develop a multi-functional adenovirus vector that combines both imaging and targeted therapy. We will provide a combination of modifications that are optimal for cell-specific adenovirus targeting in metastatic colon cancer gene therapy and for monitoring adenovirus biodistribution by non- invasive SPECT and PET imaging.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA154697-04
Application #
8699507
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Farahani, Keyvan
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Dmitriev, Igor P; Kashentseva, Elena A; Kim, Kenneth H et al. (2014) Monitoring of biodistribution and persistence of conditionally replicative adenovirus in a murine model of ovarian cancer using capsid-incorporated mCherry and expression of human somatostatin receptor subtype 2 gene. Mol Imaging 13:
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Alberti, M O; Deshane, J S; Chaplin, D D et al. (2013) A myeloid cell-binding adenovirus efficiently targets gene transfer to the lung and escapes liver tropism. Gene Ther 20:733-41
Kaliberov, Sergey A; Kaliberova, Lyudmila N; Hong Lu, Zhi et al. (2013) Retargeting of gene expression using endothelium specific hexon modified adenoviral vector. Virology 447:312-25