The molecular definition of tumor antigens has generated considerable enthusiasm for peptide-based cancer vaccines. As clinical efficacy remains limited, the focus of our research group is peptide-based cancer vaccine development. Using our innovative adoptive transfer model we have developed pre-clinical data for a novel vaccine delivery system that augments the primary T cell response via sustained paracrine release of antigenic peptide and cytokine(s). Furthermore, we have determined that post-vaccination T cell contraction is a major response limitation. Although programmed T cell contraction has been well described, the factors that modulate this response in the post-vaccination setting are not well defined. In this application we present preliminary data to suggest that the presence of a danger signal, alterations in the tissue microenvironment, and cytokine administration post-vaccination can modulate programmed T cell contraction. Given our expertise, and the ability of our adoptive transfer model to visualize the contraction phase, we are in the unique position to further these observations. The hypothesis of this grant proposal is that successful modulation of post-vaccination programmed T cell contraction will lead to enhanced antitumor immunity. In this proposal, we will use our adoptive transfer model to precisely define the mechanisms of programmed T cell contraction and the impact of specific danger signals (alpha GalCer and poly I:C) on this process. We will characterize the role of tissue microenvironment and altered T cell trafficking on post-vaccination T cell contraction and describe the impact of myeloablative conditioning regimens on the same. Further, we will delineate the impact of postvaccination systemic cytokine administration (IL-2, IL-15, and type 1 interferon) on programmed T cell contraction and define the impact of dose, timing of administration, and combination therapy on vaccine efficacy. We will then validate the most efficacious of these approaches in the poorly immunogenic TRP-2 murine melanoma model. Defining the factors that modulate programmed T cell contraction will provide critical information required for the design of more effective peptide vaccine strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA083672-06S1
Application #
7226938
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ogunbiyi, Peter
Project Start
1999-11-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
6
Fiscal Year
2006
Total Cost
$125,799
Indirect Cost
Name
Medical University of South Carolina
Department
Surgery
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Rubinstein, Mark P; Cloud, Colleen A; Garrett, Tracy E et al. (2012) Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 214:700-7; discussion 707-8
Salem, Mohamed L; Al-Khami, Amir A; El-Nagaar, Sabry A et al. (2012) Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide. Cell Immunol 276:67-74
Díaz-Montero, C Marcela; Naga, Osama; Zidan, Abdel-Aziz A et al. (2011) Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory. Am J Cancer Res 1:882-96
Salem, Mohamed L; Demcheva, Marina; Gillanders, William E et al. (2010) Poly-N-acetyl glucosamine gel matrix as a non-viral delivery vector for DNA-based vaccination. Anticancer Res 30:3889-94
Salem, Mohamed L; Al-Khami, Amir A; El-Naggar, Sabry A et al. (2010) Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. J Immunol 184:1737-47
Salem, Mohamed L; El-Naggar, Sabry A; Cole, David J (2010) Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol 261:134-43
Salem, Mohamed Labib; Cole, David J (2010) Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother 59:341-53
Rubinstein, M P; Salem, M L; Kadima, A N et al. (2009) Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo. Cancer Gene Ther 16:171-83
Diaz-Montero, C Marcela; Salem, Mohamed Labib; Nishimura, Michael I et al. (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49-59
Salem, Mohamed L; Díaz-Montero, C Marcela; Al-Khami, Amir A et al. (2009) Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol 182:2030-40

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