We have previously characterized the molecular chaperone function of a new stress protein, HSP110. We have shown that HSP110 is highly efficient in binding to substrate proteins, including tumor antigens such as HER-2/neu, by heat shock. The heat shock complex of HSP110 with the intracellular domain (ICD) of HER- 2/neu generated effective antigen-specific immune responses in a transgenic mouse model for human breast cancer. Although this immunity was capable of inhibition of the mammary tumors, complete eradication of the tumor requires an improvement in the HSP110-ICD vaccine formulation. Others (Reilly et al., 2001; Foy et al., 2002; Wolpoe et al., 2003) have reported that collaboration of both cellular and humoral HER-2/neu-targeted immune responses is required for eradication of mammary tumors. To achieve this goal, using the powerful immunoadjuvant activity of HSP110, we propose to design and evaluate a combinational vaccine of ICD plus BCD (extracellualr domain of HER-2/neu) in a chaperone complex with HSP110. We predict that generation of a strong cellular (by HSP110-ICD) and humoral (by HSP110-ECD) HER-2/neu-targeted immune responses may prevent and/or eradicate neu-overexpressing mammary tumors in a FVB-neu transgenic mouse model of human breast cancer. This hypothesis will be evaluated in Aim 1. In addition, the presence of CD4+ CD25+ regulatory T cells in breast cancer patients and FVB-neu transgenic mice may contribute to the progression of mammary tumors and failure of immunotherapy. We have recently shown that tumor-bearing animals reveal elevated CD4+ CD25+ regulatory T cells (Manjili et al., 2003). Therefore, in Aim 2, we will determine immunosuppressive function of regulatory T cells, and design and evaluate strategies, including this combinational HSP110 vaccine approach, to overcome the immunosuppressive function of regulatory T cells. The characterization of this HSP110-HER-2/neu vaccine can be expected to define new strategies for HER-2/neu-based immunotherapy of breast cancer and to have important clinical application.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CII (01))
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
Ascierto, Maria Libera; Kmieciak, Maciej; Idowu, Michael O et al. (2012) A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat 131:871-80
Kmieciak, Maciej; Basu, Debasmita; Payne, Kyle K et al. (2011) Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol 187:708-17
Manjili, Masoud H (2011) Revisiting cancer immunoediting by understanding cancer immune complexity. J Pathol 224:5-9
Kmieciak, Maciej; Worschech, Andrea; Nikizad, Hooman et al. (2011) CD4+ T cells inhibit the neu-specific CD8+ T-cell exhaustion during the priming phase of immune responses against breast cancer. Breast Cancer Res Treat 126:385-94
Kmieciak, Maciej; Toor, Amir; Graham, Laura et al. (2011) Ex vivo expansion of tumor-reactive T cells by means of bryostatin 1/ionomycin and the common gamma chain cytokines formulation. J Vis Exp :
Gowda, Madhu; Godder, Kamar; Kmieciak, Maciej et al. (2011) Distinct signatures of the immune responses in low risk versus high risk neuroblastoma. J Transl Med 9:170
Kmieciak, Maciej; Payne, Kyle K; Idowu, Michael O et al. (2011) Tumor escape and progression of HER-2/neu negative breast cancer under immune pressure. J Transl Med 9:35
Morales, Johanna K; Kmieciak, Maciej; Knutson, Keith L et al. (2010) GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells. Breast Cancer Res Treat 123:39-49
Morales, Johanna K; Kmieciak, Maciej; Graham, Laura et al. (2009) Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunol Immunother 58:941-53
Kmieciak, Maciej; Gowda, Madhu; Graham, Laura et al. (2009) Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function. J Transl Med 7:89

Showing the most recent 10 out of 19 publications