Cyclin B-1 As a Tumor-specific Antigen in Oral Carcinoma

$129,469P01FY2002DENIH

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION: (provided by applicant) For active specific immunotherapy to become a reality, tumor specific antigens must be identified. A new antigen discovery system was used based on in vitro grown human dendritic cells presenting peptides purified by HPLC from class I molecules of human tumors to healthy naive CD8+ and CD4+ T cells. They identified several immunostimulatory peptides and determined they were derived from cycling B1 protein. They also found cyclin B1 specific T cells in patients with head and neck cancer whose tumors overexpressed this protein. Further studies showed that cyclin B1 is overexpressed in a large number of human tumors, including those of the head and neck, and that this overexpression is a result of in activation of p53 function. Based on these results, they hypothesize that cyclin B1 may be a good target of an immune response in oral cancer and that cyclin B1 protein and peptides derived from it would be good candidates for oral cancer vaccines. They propose to test this hypothesis by conducting in vitro and pre-clinical studies in vivo in mouse models. In specific aim 1, they will use recombinant cyclin B1 protein to evaluate its potential to elicit not only CTL responses but also helper T cell responses. In vitro priming will be employed using dendrite cells loaded with the whole protein or individual peptides to generate T cells specific for this antigen and to identify as large a repertoire as possible of cyclin B1 peptides stimulatory to both CD8+ and CD4+ cells. In specific aim 2, they will test the potential of cyclin B1 to be a tumor rejection antigen in vivo. They will utilize the p53 knockout mouse as a model of cancer prevention and cancer therapy of spontaneous tumors though vaccination with cyclin B1. They will also employ a transplantable tumor model of a mouse squamous cell carcinoma that grows in the oral cavity.

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