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Blood, 1 November 2004, Vol. 104, No. 9, pp. 2704-2713. Prepublished online as a Blood First Edition Paper on July 6, 2004; DOI 10.1182/blood-2003-12-4319. This Article Full Text (PDF) All Versions of this Article: 2003-12-4319v1 104/9/2704    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Tang, Y. Articles by Deisseroth, A. B Search for Related Content PubMed PubMed Citation Articles by Tang, Y. Articles by Deisseroth, A. B Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 30, 2003 Accepted June 2, 2004 Multi-Step Process Through Which Adenoviral Vector Vaccine Overcomes Anergy to Tumor Associated Antigens Yucheng Tang, Lixin Zhang, Jing Yuan, Hakan Akbulut, Jonathan Maynard, Phyllis-Jean Linton, and Albert B Deisseroth* Sidney Kimmel Cancer Center, San Diego, CA, USA * Corresponding author; email: adeisseroth{at}skcc.org. The development of an immune response to cancer cells is limited by poor delivery of tumor associated antigens (TAA) to dendritic cells (DCs), and the presence on the tumor cells of self antigens to which the immune response system has developed tolerance. We have previously reported (1) that the subcutaneous injection of an adenoviral vector (Ad-sig-TAA/ecdCD40L) encoding a TAA linked to the extracellular domain (ecd) of the CD40 ligand (CD40L) can overcome the anergy which exists in tumor hosts against TAA. Our goal in the present work was to characterize the multiple steps that are involved in overcoming the anergy which exists in tumor hosts to TAA. Our studies showed that the subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector resulted in the secretion of the TAA/ecdCD40L protein for at least 10 days from the infected cells around the injection site. The binding of the TAA/ecdCD40L protein to DCs resulted in induction of expression of the CCR-7 chemokine receptor and cytokine release. This was followed by migration of the DCs from the injection site to regional lymph nodes. Tetramer staining, ELISPOT assay, and cytotoxicity assays all showed that the subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector increased the levels of splenic CD8+ T cells which were specific for the two TAA (human MUC1 and HPV E7) tested. Vaccination of mice transgenic for the hMUC1 antigen with the Ad-sig-hMUC1/ecdCD40L vector suppressed the growth of human MUC1 (hMUC1) antigen positive tumor cells in 100% of the test mice which were previously anergic to the hMUC1 antigen. The immune resistance to the hMUC1 positive tumor cells induced by the Ad-sig-TAA/ecdCD40L vector lasted up to a year and was shown to be antigen specific, HLA restricted, and to involve induction of the MAP kinase proliferation signal induction pathway. Importantly, although injection of the Ad-sig-TAA/ecdCD40L vector could induce a long lasting immune response against TAA, the administration of the TAA/ecdCD40L protein without first giving the Ad-sig-TAA/ecdCD40L vector, did not overcome the anergy that exists to TAA anywhere near as well as did the Ad-sig-TAA/ecdCD40L vector injections. These data suggest that the Ad-sig-TAA-ecd/ecdCD40L vector injections may be of value in the treatment of the many epithelial malignancies in which TAA like hMUC1 are over expressed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Your Ad here: optimizing adenoviral vector-based vaccines H. Kim Lyerly Blood 2004 104: 2612-2613. [Full Text] [PDF] This article has been cited by other articles: Y. Tang, H. Akbulut, J. Maynard, L. Petersen, X. Fang, W.-W. Zhang, X. Xia, J. Koziol, P.-J. Linton, and A. Deisseroth Vector Prime/Protein Boost Vaccine That Overcomes Defects Acquired during Aging and Cancer J. Immunol., October 15, 2006; 177(8): 5697 - 5707. [Abstract] [Full Text] [PDF] H. Akbulut, Y. Tang, K. G. Akbulut, J. Maynard, L. Zhang, and A. Deisseroth Antitumor immune response induced by i.t. injection of vector-activated dendritic cells and chemotherapy suppresses metastatic breast cancer. Mol. Cancer Ther., August 1, 2006; 5(8): 1975 - 1985. [Abstract] [Full Text] [PDF]

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