A principal goal of active immunotherapy is to mobilize the immune response against cancer. The ability of host immunity to recognize and destroy tumor cells is well established. However, attempts to activate host anti-tumor immune responses have been only partially successful. Frequently CD8+ T cells are expanded and even infiltrate tumor beds, but tumor evasion mechanisms block their ability to destroy growing cancers. The immune modulatory antibody, B7-DC XAb, was isolated from a Mayo Clinic patient with Waldenstrom's macroglobulinemia. This antibody activates both mouse and human dendritic cells in a manner distinct from other known immune activators, rapidly reprogramming T regulatory cells into effectors and potentiating T cell cytotoxic responses that can recognize and kill tumor cells. Treatment of animals with the immune modulator prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer, demonstrating the potential application of this reagent to the treatment of a wide variety of cancers. Remarkably, when B7-DC XAb was given to animals in conjunction with a partially effective vaccine, animals prone to the development of spontaneous and aggressive breast tumors remained cancer free. Experiments using mouse models are proposed (1) to determine the origin of CTL precursors that are licensed as killer cells by B7-DC XAb-activated dendritic cells, (2) to characterize the mechanisms governing DC activation and mobilization of T cell immunity by the immune modulator B7-DC XAb, and (3) to evaluate how B7-DC XAb treatment functions in established breast and ovarian carcinoma. These studies are highly relevant to the development of an immunotherapy strategy for the treatment of human cancers because the immune potentiator being studied is a human antibody that binds to and stimulates human dendritic cells by activating similar signaling pathways to those originally defined in the mouse. Furthermore, human dendritic cells activated by B7-DC XAb-treatment display similar functional properties to those seen in the mouse, including enhanced antigen uptake, the patterns in cytokine release, and an enhanced ability to activate tumor specific cytotoxic T cells.

Public Health Relevance

A new immune modulatory antibody, called B7-DC XAb, activates both mouse and human immunity in a manner distinct from other known immune activators and rapidly potentiates cellular responses that can recognize and kill cancers. Treatment of cancer bearing animals with the immune modulating antibody prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer. Experiments are proposed using animal models and human ovarian cancer to determine how this new treatment works and to define how best to use it in settings that closely mimic the spontaneous development of human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
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