Human sHIgM12 antibody (Ab) activates mouse and human dendritic cells (DCs) by cross-linking the co-stimulatory molecule B7-DC. DCs treated with sHIgM12 Ab do not undergo maturation, distinguishing this activation state from those achieved by engaging the CD40, TNF-, and the toll-like receptors. Antigen-pulsed DCs treated with sHIgM12 induce robust activation of naive T cells. Remarkably, systemic Ab treatment induces an immune-mediated protective response against a lethal challenge of B16 melanoma and promotes resistance against developing tumor nodules in a lung metastasis model. The Ab appears to induce signals directly in DCs, promoting a variety of changes including robust activation of NF-KappaB, increased resistance to apoptosis, and upregulation of cytokines, including IL-12. The current experimental aims are: (1) To determine the mechanism of protection from B16 melanoma induced by treatment of mice with B7-DC cross-linking Ab. We will evaluate the hypothesis that systemic treatment of mice with sHIgM12 Ab leads to the activation of effector T, NK, and B cells, promoting tumor killing mediated by classical effector molecules. (2) To evaluate therapeutic strategies designed to enhance multiple steps in the immune response. Current therapeutic strategies are only partially protective. Experiments are proposed to enhance this novel strategy by recruitment of DCs to the site of tumor growth with GMCSF prior to activation of DCs with B7-DC cross-linking Ab and by promoting the induced effector phase of the immune response by systemic co-stimulation with anti-41BB Ab. (3) To determine the generality of the immune protective effects of sHIgM12 Ab treatment in other tumor models: transplantable myelogenous leukemia WEHI-3B and the spontaneous breast cancer model MMT. As the sHIgM12 Ab activates DCs from multiple mouse strains, as well as human DCs, we seek to determine whether this remarkable therapeutic approach has general applicability to diverse tumor systems in disparate strains of mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104996-03
Application #
7013208
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Howcroft, Thomas K
Project Start
2004-02-23
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$236,215
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bell, Michael P; Pavelko, Kevin D (2016) Enhancing the Tumor Selectivity of a Picornavirus Virotherapy Promotes Tumor Regression and the Accumulation of Infiltrating CD8+ T Cells. Mol Cancer Ther 15:523-30
Grahn, Peter J; Lee, Kendall H; Kasasbeh, Aimen et al. (2015) Wireless control of intraspinal microstimulation in a rodent model of paralysis. J Neurosurg 123:232-242
Bell, Michael P; Renner, Danielle N; Johnson, Aaron J et al. (2014) An elite controller of picornavirus infection targets an epitope that is resistant to immune escape. PLoS One 9:e94332
Bell, Michael P; Renner, Danielle N; Johnson, Aaron J et al. (2014) A CD8 T-cell epitope variant enhances immune targeting to a recombinant picornavirus vaccine antigen. Viral Immunol 27:361-6
Pavelko, Kevin D; Bell, Michael P; Karyampudi, Lavakumar et al. (2013) The epitope integration site for vaccine antigens determines virus control while maintaining efficacy in an engineered cancer vaccine. Mol Ther 21:1087-95
Pavelko, Kevin D; Girtman, Megan A; Mitsunaga, Yoshihiro et al. (2011) Theiler's murine encephalomyelitis virus as a vaccine candidate for immunotherapy. PLoS One 6:e20217
Xu, Xiaohua; Warrington, Arthur E; Bieber, Allan J et al. (2011) Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network. CNS Drugs 25:555-73
(2010) Retraction: Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions. PLoS One 5:
Wiehagen, Karla R; Pulko, Vesna; Van Keulen, Virginia et al. (2010) Retraction: Induction of a Th1 response from Th2-polarized T cells by activated dendritic cells: dependence on TCR:peptide-MHC interaction, ICAM-1, IL-12, and IFN-gamma. J Immunol 184:6555
Nguyen, Loc T; Ciric, Bogoljub; Ure, Daren R et al. (2010) Retraction: Naturally occurring human IgM antibody that binds B7-DC and potentiates T cell stimulation by dendritic cells. J Immunol 184:6552

Showing the most recent 10 out of 26 publications