The major goal of the proposed studies is to test the hypothesis that a recombinant adenovirus expressing the tumor associated antigen GA733 (Ad.GA733-2) can be utilized to elicit a GA733 antigen-specific immune response in patients with metastatic colorectal cancer. The first step will be to produce Ag.GA733-2 for clinical use and to perform preclinical toxicity studies. Administration of Ag.GA733-2 and the mouse homologue Ad.mEGP will be performed in BALB/C mice. The intraperitoneal route will be utilized for the preclinical and clinical studies unless ongoing and future experiments demonstrate that the intradermal/subcutaneous route is efficacious. A range of virus doses will be tested in these animals. We will define the toxicity of this therapy by clinical parameters as well as necropsy. We will then perform a phase I study of intraperitoneal injection of Ad.GA733-2 in humans with metastatic colorectal cancer. We will define the toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will define the toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will attempt to determine the dose-limiting toxicities of this treatment in humans at a range of dose levels as determined in the preclinical toxicity testing. We will attempt to determine the dose-limiting toxicities and the mechanisms of toxicity of this treatment. As well, all patients treated will undergo extensive immunologic testing to determine the ability of intraperitoneal vaccination with Ad.GA733-2 to induce humoral and/or cellular immune responses (Project 4). We will also assess objective anti-tumor responses in these patients. Subsequent vaccination trials in metastatic colorectal cancer patients will be based upon the results of this phase I trial and Project 2. We anticipate, based on preliminary data obtained in mice, to conduct a subsequent phase I trial that focuses upon the combination of Ad.GA733-2 and interleukin-2. Future phase I trials may incorporate new vaccination strategies derived from Projects 1,2, and 4.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA074294-03
Application #
6300547
Study Section
Project Start
2000-01-01
Project End
2000-12-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$154,053
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Berencsi, Klara; Rani, Pyapalli; Zhang, Tianqian et al. (2011) In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2. J Transl Med 9:33
Swoboda, Rolf K; Somasundaram, Rajasekharan; Caputo, Laura et al. (2010) Nucleophosmin is recognized by a cytotoxic T cell line derived from a rectal carcinoma patient. Int J Cancer 127:1124-30
Kalabis, Jiri; Li, Gang; Fukunaga-Kalabis, Mizuho et al. (2008) Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium. Am J Physiol Gastrointest Liver Physiol 295:G1182-9
Berencsi, Klara; Meropol, Neal J; Hoffman, John P et al. (2007) Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture. Cancer Immunol Immunother 56:359-70
Furth, Emma E; Li, Jian; Purev, Enkhtsetseg et al. (2006) Serum antibodies to EpCAM in healthy donors but not ulcerative colitis patients. Cancer Immunol Immunother 55:528-37
Gutzmer, Ralf; Li, Wei; Sutterwala, Shaheen et al. (2004) A tumor-associated glycoprotein that blocks MHC class II-dependent antigen presentation by dendritic cells. J Immunol 173:1023-32
Birebent, Brigitte; Mitchell, Edith; Akis, Nese et al. (2003) Monoclonal anti-idiotypic antibody mimicking the gastrointestinal carcinoma-associated epitope CO17-1A elicits antigen-specific humoral and cellular immune responses in colorectal cancer patients. Vaccine 21:1601-12
Schaider, Helmut; Oka, Masahiro; Bogenrieder, Thomas et al. (2003) Differential response of primary and metastatic melanomas to neutrophils attracted by IL-8. Int J Cancer 103:335-43
Armstrong, Andrew; Eck, Stephen L (2003) EpCAM: A new therapeutic target for an old cancer antigen. Cancer Biol Ther 2:320-6
Zaloudik, Jan; Li, Weiping; Jacob, Lutz et al. (2002) Inhibition of tumor growth by recombinant vaccinia virus expressing GA733/CO17-1A/EpCAM/KSA/KS1-4 antigen in mice. Cancer Gene Ther 9:382-9

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