Novel adjuvant therapies for head and neck cancer (HNC) are urgently needed, since the survival from this disease has not improved significantly in over 30 years. Recent advances in the development of antitumor vaccines have created an opportunity for evaluation of such vaccines in patients with SCCHN. In general, many shared human tumor antigens are derived from proteins overexpressed in tumors relative to normal cells. Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers, but mutant p53-based immunotherapy would require 'custom made' vaccines for use in relatively few patients. Since most mutations of p53, however, are associated with accumulation or 'over expression' of mutant p53 in the tumor cytosol, the protein is readily accessible to degradation into peptides for immune recognition. Thus, a vaccine targeting wt p53 peptides derived not from the specific mutations but from normal epitopes in the altered p53 molecules appears to be a more attractive approach to developing broadly applicable p53-based cancer vaccines. Based on our preliminary results, we propose a phase I clinical trial of a DC-based multi-epitope wt p53 vaccine that contains two HLA-A*0201 (HLA-A2.1)-restricted Tcell- defined p53 peptides plus either a wt p53 or nonspecific helper peptide. This project also includes extensive ex vivo immunological analyses of the SCCHN patients' responses to immunization as well as tumor characterization to determine whether the tumor is capable of presenting the targeted wt p53 epitopes. Preclinical work developing another wt p53 T helper peptide, with broader HLA binding will also be performed. Results from the in vitro analyses and immunologic responses to the phase I vaccine trial will be combined to facilitate the continued development of p53-based immunotherapy for SCCHN, enabling the design of a future phase II wt p53-based vaccine trial.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA097190-01A1
Application #
6990396
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (M1))
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$153,880
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ma, Jing; Salamoun, Joseph; Wipf, Peter et al. (2018) Combination of a thioxodihydroquinazolinone with cisplatin eliminates ovarian cancer stem cell-like cells (CSC-LCs) and shows preclinical potential. Oncotarget 9:6042-6054
Hartman, Douglas J; Ahmad, Fahad; Ferris, Robert L et al. (2018) Utility of CD8 score by automated quantitative image analysis in head and neck squamous cell carcinoma. Oral Oncol 86:278-287
Pai, Sara I; Jack Lee, J; Carey, Thomas E et al. (2018) HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers. Oral Oncol 77:92-97
Shayan, Gulidanna; Kansy, Benjamin A; Gibson, Sandra P et al. (2018) Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 Stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals. Clin Cancer Res 24:62-72
Lee, Yoon Se; Johnson, Daniel E; Grandis, Jennifer R (2018) An update: emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs :1-17
Johnson, Daniel E; O'Keefe, Rachel A; Grandis, Jennifer R (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234-248
Close, David A; Camarco, Daniel P; Shan, Feng et al. (2018) The Generation of Three-Dimensional Head and Neck Cancer Models for Drug Discovery in 384-Well Ultra-Low Attachment Microplates. Methods Mol Biol 1683:355-369
Yang, Xi; Xia, Rui; Yue, Cuihua et al. (2018) ATF4 Regulates CD4+ T Cell Immune Responses through Metabolic Reprogramming. Cell Rep 23:1754-1766
Njatcha, Christian; Farooqui, Mariya; Kornberg, Adam et al. (2018) STAT3 Cyclic Decoy Demonstrates Robust Antitumor Effects in Non-Small Cell Lung Cancer. Mol Cancer Ther 17:1917-1926
Johnston, Paul A; Sen, Malabika; Hua, Yun et al. (2018) High Content Imaging Assays for IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines. Methods Mol Biol 1683:229-244

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