Abstract

The recent identification of several tumor-derived T-cell epitopes has provided crucial reagents for the design and implementation of peptide-based therapy protocols for the treatment of patients with certain cancers (i.e., melanoma). These trials are currently hampered due to indecision on the proper choice of peptide adjuvant and relevant immune parameters to be evaluated. The applicant has examined tumor peptide vaccines in a series of established murine tumor models and has shown dramatic tumor regressions using therapies consisting of i.v. inoculation of IL-4 + GM-CSF cultured bone marrow (BM) dendritic cells (DC) pulsed with tumor-derived peptides. Peptides may be either synthetic or unfractionated material removed from tumor cells by mild acid-elution. The therapeutic efficacy of DC/unfractionated tumor peptide vaccines involves both CD4+ and CD8+ lymphocytes, the cytokines IFN-gamma and TNF-alpha, and the CD28/CTLA T- cell costimulatory signalling pathway. Furthermore, successful DC/tumor peptide therapy was associated with pronounced perilesional infiltration with S-100+ host tissue DC. These results support the development of DC/tumor peptide-based therapies for human cancer. In order to develop these clinical trials in a rational manner the applicant proposes to:
AIM 1. Establish the most effective means to apply DC/tumor peptide- based therapies in the treatment of established murine tumors and delineate the relevant immune mechanisms involved, AIM 2. Evaluate the efficacy and mechanism of action of gene-engineered DC/tumor peptide- based therapies for the treatment of established tumors, AIM 3. Evaluate the effectiveness of DC/tumor peptide- based therapy against established tumors of common genetic background and histology, but divergent in immunogenicity/tumorigenicity, AIM 4. Identify peptide species from murine BL6-class I+ variant melanoma recognized by specific CTL for use in DC-based therapies, and AIM 5. Develop clinical trials for the implementation of DC/tumor peptide-based therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063350-04
Application #
2871829
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
1996-04-09
Project End
2001-01-31
Budget Start
1999-02-16
Budget End
2000-01-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Sasaki, Kotaro; Pardee, Angela D; Qu, Yanyan et al. (2009) IL-4 suppresses very late antigen-4 expression which is required for therapeutic Th1 T-cell trafficking into tumors. J Immunother 32:793-802
Sasaki, Kotaro; Zhao, Xi; Pardee, Angela D et al. (2008) Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo. J Immunol 181:104-8
Sasaki, Kotaro; Pardee, Angela D; Okada, Hideho et al. (2008) IL-4 inhibits VLA-4 expression on Tc1 cells resulting in poor tumor infiltration and reduced therapy benefit. Eur J Immunol 38:2865-73
Berhanu, Aklile; Huang, Jian; Watkins, Simon C et al. (2007) Treatment-enhanced CD4+Foxp3+ glucocorticoid-induced TNF receptor family related high regulatory tumor-infiltrating T cells limit the effectiveness of cytokine-based immunotherapy. J Immunol 178:3400-8
Berhanu, Aklile; Huang, Jian; Alber, Sean M et al. (2006) Combinational FLt3 ligand and granulocyte macrophage colony-stimulating factor treatment promotes enhanced tumor infiltration by dendritic cells and antitumor CD8(+) T-cell cross-priming but is ineffective as a therapy. Cancer Res 66:4895-903
Bjorck, P; Coates, P T H; Wang, Z et al. (2005) Promotion of long-term heart allograft survival by combination of mobilized donor plasmacytoid dendritic cells and anti-CD154 monoclonal antibody. J Heart Lung Transplant 24:1118-20
Huang, Jian; Tatsumi, Tomohide; Pizzoferrato, Eva et al. (2005) Nitric oxide sensitizes tumor cells to dendritic cell-mediated apoptosis, uptake, and cross-presentation. Cancer Res 65:8461-70
Bjorck, Pia (2004) Dendritic cells exposed to herpes simplex virus in vivo do not produce IFN-alpha after rechallenge with virus in vitro and exhibit decreased T cell alloreactivity. J Immunol 172:5396-404
Tatsumi, Tomohide; Huang, Jian; Gooding, William E et al. (2003) Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer Res 63:6378-86
Tatsumi, Tomohide; Gambotto, Andrea; Robbins, Paul D et al. (2002) Interleukin 18 gene transfer expands the repertoire of antitumor Th1-type immunity elicited by dendritic cell-based vaccines in association with enhanced therapeutic efficacy. Cancer Res 62:5853-8

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