Localized immunotherapeutic approaches to cancer have been effective in treating tumors such as melanoma and bladder carcinoma, although the mechanism of action of such therapies as intravesical or intralesional BCG has eluded definition. While localized mechanisms which result in tumor elimination contribute to therapeutic success, optimal anti-tumor effectiveness, particularly at disseminated tumor sites, requires the development of systemic immunity which must be the goal of any new therapy. Using a murine model of orthotopic bladder tumor growth, the studies outlined in this proposal are aimed at developing strategies for the development of systemic anti-tumor immunity following immunotherapy designed to result in lymphocyte activation at the tumor site. The overall hypothesis of the proposal is that by modulating the immune milieu at the local tumor site, and thus recruiting antigen-presenting and effector cell populations, it will be possible to engender a systemic tumor specific immune response. The result would be to eliminate both localized and disseminated tumor. Towards this end, studies have been designed which use intravesical BCG, in-vivo cytokine manipulation, and our newly developed recombinant vaccinia gene therapy approaches to assess the effectiveness of manipulating tumor antigenicity and the overall cytokine/lymphokine milieu on developing tumor-specific immunity. While these studies utilize a bladder tumor model, the results obtained, particularly using our new vaccinia methodology, will be directly applicable to a variety of tumors, allowing in-situ manipulation of the localized immune """"""""environment"""""""" and, we anticipate, the generation of systemic anti-tumor immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042908-10
Application #
2007585
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1987-05-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
10
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Sharp, Daniel W; Lattime, Edmund C (2016) Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization. Biomedicines 4:
de Vries, C R; Monken, C E; Lattime, E C (2015) The addition of recombinant vaccinia HER2/neu to oncolytic vaccinia-GMCSF given into the tumor microenvironment overcomes MDSC-mediated immune escape and systemic anergy. Cancer Gene Ther 22:154-62
Nikitczuk, Kevin P; Schloss, Rene S; Yarmush, Martin L et al. (2013) PLGA-polymer encapsulating tumor antigen and CpG DNA administered into the tumor microenvironment elicits a systemic antigen-specific IFN-? response and enhances survival. J Cancer Ther 4:280-290
Moloughney, Joseph G; Monken, Claude E; Tao, Hanlin et al. (2011) Vaccinia virus leads to ATG12–ATG3 conjugation and deficiency in autophagosome formation. Autophagy 7:1434-47
Nikitczuk, Kevin P; Lattime, Edmund C; Schloss, Rene S et al. (2010) ANALYSIS OF DENDRITIC CELL STIMULATION UTILIZING A MULTI-FACETED NANOPOLYMER DELIVERY SYSTEM AND THE IMMUNE MODULATOR 1-METHYL TRYPTOPHAN. Nano Life 1:239-250
Yang, Arvin S; Lattime, Edmund C (2003) Tumor-induced interleukin 10 suppresses the ability of splenic dendritic cells to stimulate CD4 and CD8 T-cell responses. Cancer Res 63:2150-7
Yang, Arvin S; Monken, Claude E; Lattime, Edmund C (2003) Intratumoral vaccination with vaccinia-expressed tumor antigen and granulocyte macrophage colony-stimulating factor overcomes immunological ignorance to tumor antigen. Cancer Res 63:6956-61
Mastrangelo, Michael J; Lattime, Edmund C (2002) Virotherapy clinical trials for regional disease: in situ immune modulation using recombinant poxvirus vectors. Cancer Gene Ther 9:1013-21
Mastrangelo, M J; Eisenlohr, L C; Gomella, L et al. (2000) Poxvirus vectors: orphaned and underappreciated. J Clin Invest 105:1031-4
Mastrangelo, M J; Maguire Jr, H C; Eisenlohr, L C et al. (1999) Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 6:409-22

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