Carbohydrate antigens are the most abundantly expressed antigens on the cell surface of most cancers and several have been shown to function as effective targets for active and passive specific immunotherapy in clinical trials. Previous studies of biopsy specimens have shown that most breast Cancers express at the cell surface the Thomsen-Friedenreich (TF), sialyl Tn (sTn), Lewis- (Le) and Globo H carbohydrate antigens, and the peptide antigen MUCI. Conjugate Vaccines have proven the most effective approach to augmenting the antibody response against carbohydrate and peptide antigens in our experience. Keyhole limpet hemocyanin (KLH) has been the most potent carrier molecule and the saponin fraction QS-2l the most potent immunological adjuvant. We have completed accrual to a pilot trial with a MUCl-KLH plus QS21 vaccine in patients with breast cancer and recently initiated a pilot trial with an sTn(c )-KLH vaccine in this same patient population. The sTn(c) trial is based on our recent observation that the antigen recognized by monoclonal antibody B72.3 is sTn expressed in a cluster conformation [sTn(c)]. TF, Le and Globo H antigens have been synthesized, conjugated to KLH, and relevant immunogenicity has been confirmed in the mouse. In this proposal, we seek to test the immunogenicity of these single antigen vaccines in Phase I/II studies in breast cancer patients, to construct a consistently immunogenic polyvalent vaccine, and to test this for immunogenicity and toxicity. A large multicenter randomized Phase III clinical trial will be initiated in the second half of year three in patients with Stage 2 or 3 breast Cancer who are free of detectable disease after adjuvant chemotherapy but are at high risk of developing recurrent disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA061422-04
Application #
2008350
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1994-05-02
Project End
2000-02-29
Budget Start
1997-05-01
Budget End
1998-02-28
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Gilewski, Teresa A; Ragupathi, Govind; Dickler, Maura et al. (2007) Immunization of high-risk breast cancer patients with clustered sTn-KLH conjugate plus the immunologic adjuvant QS-21. Clin Cancer Res 13:2977-85
Ragupathi, Govindaswami; Deshpande, Prashant P; Coltart, Don M et al. (2002) Constructing an adenocarcinoma vaccine: immunization of mice with synthetic KH-1 nonasaccharide stimulates anti-KH-1 and anti-Le(y) antibodies. Int J Cancer 99:207-12
Ragupathi, G; Howard, L; Cappello, S et al. (1999) Vaccines prepared with sialyl-Tn and sialyl-Tn trimers using the 4-(4-maleimidomethyl)cyclohexane-1-carboxyl hydrazide linker group result in optimal antibody titers against ovine submaxillary mucin and sialyl-Tn-positive tumor cells. Cancer Immunol Immunother 48:1-8
Kudryashov, V; Kim, H M; Ragupathi, G et al. (1998) Immunogenicity of synthetic conjugates of Lewis(y) oligosaccharide with proteins in mice: towards the design of anticancer vaccines. Cancer Immunol Immunother 45:281-6
Zhang, S; Zhang, H S; Reuter, V E et al. (1998) Expression of potential target antigens for immunotherapy on primary and metastatic prostate cancers. Clin Cancer Res 4:295-302
Ragupathi, G; Koganty, R R; Qiu, D et al. (1998) A novel and efficient method for synthetic carbohydrate conjugate vaccine preparation: synthesis of sialyl Tn-KLH conjugate using a 4-(4-N-maleimidomethyl) cyclohexane-1-carboxyl hydrazide (MMCCH) linker arm. Glycoconj J 15:217-21
Zhang, S; Zhang, H S; Cordon-Cardo, C et al. (1998) Selection of tumor antigens as targets for immune attack using immunohistochemistry: protein antigens. Clin Cancer Res 4:2669-76
Zhang, S; Zhang, H S; Cordon-Cardo, C et al. (1997) Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. Int J Cancer 73:50-6
Zhang, S; Cordon-Cardo, C; Zhang, H S et al. (1997) Selection of tumor antigens as targets for immune attack using immunohistochemistry: I. Focus on gangliosides. Int J Cancer 73:42-9
Zhang, S; Graeber, L A; Helling, F et al. (1996) Augmenting the immunogenicity of synthetic MUC1 peptide vaccines in mice. Cancer Res 56:3315-9

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