More than 90 percent of cervical cancers have been associated with human papillomaviruses (HPVs). Two HPV oncogenic proteins, E6 and E7, are important in the induction and maintenance of cellular transformation and are co-expressed in most HPV- containing cervical cancers. Therefore, vaccines or immunotherapies targeting E6 and E7 proteins will provide an opportunity to prevent and treat HPV-associated cervical malignancies. The destruction of tumor cells will most likely require induction of a tumor specific cytotoxic T lymphocyte (CTL) response as well as potentially a tumor specific T helper (Th) response. Studies in vitro indicate that T cell responses vary qualitatively and quantitatively depending on two parameters: 1) the density of peptide-MHC complexes on the surface of antigen presenting cells, and 2) the nature of co-stimulatory signals delivered to the T cell in conjunction with T cell receptor engagement. Based on this improved understanding, the applicant has identified potential strategies to optimize T cell activation by modifying both parameters in vivo. These strategies will utilize a vaccinia vector and E6 and E7 as the targeted tumor specific antigens. The broad objective of this application is to develop strategies to enhance E6 and E7 specific T cell responses by optimizing the activation of E6 and E7 specific T cells and to evaluate the potency of the vaccines in generating antitumor immunity against tumors expressing E6 and E7. Since the failure of the immune system to reject tumors is frequently attributed to insufficient CD4+ T help, the applicant will focus on strategies than enhance CD4+ helper T cell responses. Specifically, he plans to: 1) Construct recombinant vaccinia which increase the density of E6/E7 peptide MHC class II complexes by delivering chimeric E6/E7 into the MHC class II pathway. 2) Engineer double recombinant vaccines that will enable to co-expression of E6/E7 or Sig/E6/E7/LAMP-1 along with molecules capable of providing co-stimulatory signals to responding T cells. 3) Characterize the standard immunologic parameters of E6 and E7 specific responses generated by optimized recombinant vaccinia vaccines. 4) Generate E6 and E7 expressing murine tumors for in vivo protection and treatment experiments. 5) Perform head-to-head comparison of various E6, E7 and chimeric E6E7 vaccines in antitumor immunity using E6 and E7 expressing murine model tumors.
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