Dendritic cell (DC)-based immunotherapy is a promising approach for cancer treatment. Phase I clinical trials employing adoptive transfer of cultured DCs pulsed with tumor antigens ex vivo have recently been initiated. Genetic transduction of DCs represents another method of tumor antigen presentation with potential advantages over pulsing. Although several such genetic vaccine strategies show promise, optimal vectors and delivery methods are still being developed. The present proposal examines the use of recombinant adeno-associated virus (rAAV) vectors for ex vivo transduction of DCs, for the purpose of anti-tumor immunization. Potential advantages of rAAV for this application include limited host exposure to viral structural elements and stable expression of the antigen. Preliminary data indicate that transduction of ex vivo differentiated human and mouse DCs by rAAV is possible. Further, human peripheral blood monocytes transduced with rAAV and subsequently differentiated, showed robust transgene expression in the generated DCs. Based on our previous studies that transduction of recombinant adenoviral (Ad) vectors through alternate cellular pathways in DCs promote both DC-specific targeting and DC-maturation, we hypothesize that retargeting AAV vectors through the CD40 pathway will similarly promote DC-specific targeting and activation. The goals of this project are to optimize DC transduction by rAAV encoding a tumor antigen, carcinoembryonic antigen (CEA), to achieve potent T cell responses and to evaluate the efficacy of rAAV-CEA transduced DCs in antitumor activity in a mouse model in vivo. The proposed experiments will provide a necessary proof of principle in support of future trials of rAAV-CEA transduced DC vaccines for immunotherapy of CEA-positive human cancers and also will have relevance for the development of additional rAAV vaccines expressing other antigens or genes to enhance antigen-presenting functions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090850-04
Application #
6878094
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$238,569
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Ponnazhagan, Selvarangan; Mahendra, Gandham; Lima, Jose et al. (2004) Augmentation of antitumor activity of a recombinant adeno-associated virus carcinoembryonic antigen vaccine with plasmid adjuvant. Hum Gene Ther 15:856-64
Ponnazhagan, Selvarangan; Hoover, Frank (2004) Delivery of DNA to tumor cells in vivo using adeno-associated virus. Methods Mol Biol 246:237-43

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