We have generated a murine monoclonal anti-idiotype ( antibody, 3Hl, that is the internal image of the carcinoembryonic antigen (CEA). We have demonstrated that patients with advanced metastatic colorectal cancer (CRC) and patients with high risk CRC in the post-surgical adjuvant setting generate an active immune response against CEA following an adequate number of immunizations with the Chl anti-Id adsorbed to aluminum hydroxide. We demonstrated a predominantly IgG polyclonal humoral immune response with specific binding to purified CEA and CEA positive cells that mediated antibody-dependent cellular cytotoxicity. The vaccinated patients also demonstrated in vitro T cell proliferative responses in the presence of anti-Id 3Hl, CEA or synthetic peptides derived from 3H1 and CEA. While one of the patients had objective clinical response to 3Hl, several continue on vaccine therapy with stable disease from 12-36 months. Toxicity was limited to local reactions at the site of the injection with mild fevers. In this project, we will conduct clinical trials in which patients with Dukes B and C colorectal carcinoma will be treated with adjuvant 5FU and leucovorin and anti-Id 3Hl in combination with different immunologic adjuvants such as GS-21, GM-CSF or low-dose IL-2. The patients will be observed for immune responses and for clinical outcome. Animal models in C57BL/6 mice transplanted with the human CEA transfected murine colon cancer cell line MC38 will be used to develop more powerful methods of immunization utilizing the anti-Id 3Hl derivatives and to dissect the mechanisms of anti-tumor immunity. We will investigate a single chain Fv molecule (scFv) of 3Hl as an immunogen mixed with variety of adjuvants and cytokines. We will investigate the role of dendritic cell (DC) in developing tumor immunity after pulsing them with relevant anti-idiotypic reagents. In addition, adenoviral vectors (AdV) will be used to introduce 3H1-scFv or CEA into DC, which in turn will be tested for vaccine potential. We will also generate potentially therapeutic DC from leukapheresis products of CRC patients (some of them may be pretreated with 3H1 vaccine), and pulse them with the anti-Id 3Hl, CEA or relevant peptides or transduce them with Adv expressing these genes and examine their antigen presenting and T cell stimulatory function or T cell cytolytic function in vitro. These studies will be a prelude to clinical trials for CRC patients with autologous DC based anti-Id vaccine and scFv.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA086025-03
Application #
6377842
Study Section
Special Emphasis Panel (ZRG1-ET-1 (02))
Program Officer
Xie, Heng
Project Start
1999-09-30
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$343,020
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Saha, Asim; Baral, Rathindra Nath; Chatterjee, Sunil K et al. (2006) CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice. Cancer Immunol Immunother 55:515-27
Saha, Asim; Chatterjee, Sunil K; Foon, Kenneth A et al. (2006) Anti-idiotype antibody induced cellular immunity in mice transgenic for human carcinoembryonic antigen. Immunology 118:483-96
Saha, Asim; Chatterjee, Sunil K; Foon, Kenneth A et al. (2004) Dendritic cells pulsed with an anti-idiotype antibody mimicking carcinoembryonic antigen (CEA) can reverse immunological tolerance to CEA and induce antitumor immunity in CEA transgenic mice. Cancer Res 64:4995-5003
Saha, Asim; Chatterjee, Sunil K; Foon, Kenneth A et al. (2003) Murine dendritic cells pulsed with an anti-idiotype antibody induce antigen-specific protective antitumor immunity. Cancer Res 63:2844-54
Baral, Rathindra Nath; Saha, Asim; Chatterjee, Sunil K et al. (2003) Immunostimulatory CpG oligonucleotides enhance the immune response of anti-idiotype vaccine that mimics carcinoembryonic antigen. Cancer Immunol Immunother 52:317-27
Bhattacharya-Chatterjee, Malaya; Chatterjee, Sunil K; Foon, Kenneth A (2002) Anti-idiotype antibody vaccine therapy for cancer. Expert Opin Biol Ther 2:869-81
Bhattacharya-Chatterjee, M; Chatterjee, S K; Foon, K A (2001) The anti-idiotype vaccines for immunotherapy. Curr Opin Mol Ther 3:63-9