As CD4+ T cells are important not only for the development but also for the persistence of the anti-tumor immune responses, we have hypothesized that the failure to stimulate this CD4+ T cells may be one of the reasons why previous peptide vaccines did not induce tumor regression in a large number patients with melanoma. We have recently identified a series of MHC class II-presented melanoma epitopes recognized by CD4+ T cells. In particular, we have identified several epitopes derived from the NY-ESO-1 antigen that is commonly expressed by a broad range of tumor types, including melanomas. We now propose to perform clinical trials to assess the in vivo efficacy of cancer vaccines with T-helper epitopes in patients with melanoma. The rationale for our proposed research project is several fold and can be stated as follows:(1) vaccines integrating T-helper epitopes will optimally stimulate high-avidity tumor-reactive CTL responses capable of mediating tumor regression; (2) T-helper and CTL responses against epitopes that derive from NY-ESO-1 are less likely to be tolerized in situ since this antigen is not expressed by normal tissues; (3) CpG oligonucleotide adjuvants are expected to stimulate plasmacytoid dendritic cells (PDCs) resulting in strong Th1-type immunity; (4) modern immunologic monitoring techniques will allow us to discriminate melanoma-specific T cell responses in the blood of vaccinated patients, allowing us to assess the in vivo impact of our vaccine strategy. We propose the following aims: (1) To perform a phase I-II randomized clinical trial of NY-ESO-1-derived peptides versus recombinant NY-ESO-1 protein in patients with melanoma, using CpG 7909 as adjuvant; (2) To analyze the epitope-specificities and functions of CD8+ and CD4+ T cells from the blood of the patients undergoing peptide or protein-based vaccines in the Specific Aim 1; (3) To study the trafficking and immunostimulatory effects of plasmacytoid dendritic cells (PDCs) following vaccination with CpG + peptides or protein. While we cannot predict the results of the clinical trial proposed in Aim 1, those results should facilitate a better understanding of the mechanisms underlying peptide-based and protein-based vaccination through skin in association with CpG 7909 for patients with melanoma. Altogether, these data will indicate whether or not one vaccination intervention in Aim 1 is superior to the others in promoting anti-NY-ESO-1 CTL responses. These data will also allow us to define additional strategies that may synergize with CpG adjuvants to further improve vaccines designed to enhance the development and durability of tumor-reactive CD8+ T cells and Th-1 type CD4+ T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112198-04
Application #
7352675
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Xie, Heng
Project Start
2005-02-01
Project End
2009-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$324,109
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien et al. (2015) TIGIT and PD-1 impair tumor antigen-specific CD8? T cells in melanoma patients. J Clin Invest 125:2046-58
Sun, Zhaojun; Fourcade, Julien; Pagliano, Ornella et al. (2015) IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells. Cancer Res 75:1635-44
Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2014) PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8? T cells induced by melanoma vaccines. Cancer Res 74:1045-55
Fourcade, Julien; Zarour, Hassane M (2013) Strategies to reverse melanoma-induced T-cell dysfunction. Clin Dermatol 31:251-6
Kirkwood, John M; Butterfield, Lisa H; Tarhini, Ahmad A et al. (2012) Immunotherapy of cancer in 2012. CA Cancer J Clin 62:309-35
Kudela, Pavol; Sun, Zhaojun; Fourcade, Julien et al. (2011) Epitope hierarchy of spontaneous CD4+ T cell responses to LAGE-1. J Immunol 186:312-22
Fourcade, Julien; Sun, Zhaojun; Benallaoua, Mourad et al. (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175-86
Fourcade, Julien; Sun, Zhaojun; Kudela, Pavol et al. (2010) Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J Immunol 184:6709-18
Fourcade, Julien; Kudela, Pavol; Sun, Zhaojun et al. (2009) PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 182:5240-9
Fourcade, Julien; Kudela, Pavol; Andrade Filho, Pedro A et al. (2008) Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J Immunother 31:781-91

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