Recent studies in our laboratory have identified a unique mode of antigen recognition by T cells that may be adapted to augment specific recognition of tumor-associated antigens. Our studies have shown that the autoreactive T cells from Cyclosporine-induced autologous graft-vs-host disease recognize a peptide from the MHC class II invariant chain termed CLIP. Although the autoreactive T cells recognize CLIP, in part, via a classic mechanism, there also appears to be a functional superantigen-like interaction betwteen the N-terminal flanking region of CLIP that extends beyond the peptide binding groove of MHC class II and the Vbeta segment of the T cell receptor. Preliminary studies show that the addition of this flanking region of CLIP onto nominal antigenic peptides enhances their immunogenicity. The central hypothesis of this proposal, therefore, is that modification of tumor peptides by adding the N-terminal flanking region of CLIP will augment their immunogenicity and evoke a potent antitumor immune response. The present studies will focus on peptides from the oncogene, C-erbB-2 also known as Her-2/neu as a model system. This oncogene evokes a weak but ineffective immune response in patients with breast cancer. A rat model will be utilized to test this hypothesis since there is significant homology between rat and human Her-2/neu. Chimeric constructs of Her-2/neu with the N-terminal flanking region of CLIP will be utilized as a vaccine. The optimal dose and vaccine formulation (adjuvant, peptide loaded tumor cells, peptide loaded dendritic cells) that elicit the maximum immune response will be identified assessing antibody production and CD4+ and CD8+ dependent cellular immunity and whether this vaccine strategy evokes a potent antitumor response. These studies will identify novel strategies to enhance the immunogenicity of tumor peptides that may be broadly applicable to many different types of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Experimental Therapeutics Subcommittee 1 (ET)
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Hecht, Toby T
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Hess, Allan D (2010) Reconstitution of self-tolerance after hematopoietic stem cell transplantation. Immunol Res 47:143-52
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