The overall objective is to establish the paradigm that co-expression of T-helper 1 molecular adjuvants by oral DNA vaccines targeting transcription factor Fos-related antigen 1 (Fra-1) can sufficiently prime and boost T cell-mediated immune responses in spontaneous metastatic breast cancer models to test the following hypotheses: 1) that established spontaneous pulmonary metastases can be {completely} eradicated to significantly prolong the life span of BALB/c mice; 2) that the recurrence of such metastases can be (fully) prevented in a minimal residual disease setting; 3) that prophylactic vaccination can induce an effective memory T cell response leading to long-lived protection against breast tumor growth and metastasis.
The specific aims designed to test these hypotheses and to delineate as well as optimize immunological mechanisms {and signal transduction pathways} governing the mode of action of these vaccines are as follows: First, achieve optimal processing and presentation of Fra-1 by DCs and macrophages for effective priming of the immune response with expression vectors encoding Fra-1 and chemokine CCL16 followed by boosting with vectors encoding Fra-1 and secretory IL-23, all targeted to secondary lymphoid organs with attenuated Salmonella typhimurium serving as the vaccine carrier. Second, critically evaluate the efficacy of this strategy {in boosting dormant memory T cells in nonlymphoid tissues in the local tumor environment and assess their ability to kill metastatic tumor cells.} Third, {identify specific Fra-1 T cell epitopes with minigene vaccines with emphasis on the involvement of specific immunological mechanisms and signal transduction pathways underlying the prime/boost strategy to optimize DNA vaccine efficacy through the induction of a long lived memory T cell response.} Achievement of this proposal's objectives will lead to novel DNA vaccines based on rational immunological principles that may ultimately contribute to the improved treatment of breast cancer. Relevance to public health is in the proposal's deliberate translational research design resulting in preliminary data which convinced a well known oncologist to offer an early clinical evaluation of a humanized version of this breast cancer vaccine, particularly if warranted by additional compelling pre-clinical data. This allows for this vaccine to go full circle in evaluation from bench to bedside and back for further improvement. ? ? ?
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| Xiang, R; Liao, D; Cheng, T et al. (2011) Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer. Br J Cancer 104:1410-7 |
| Luo, Y P; Zhou, H; Krueger, J et al. (2010) The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression. Oncogene 29:662-73 |
| Xiang, Rong; Luo, Yunping; Niethammer, Andreas G et al. (2008) Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 222:117-28 |
| Luo, Yunping; Markowitz, Dorothy; Xiang, Rong et al. (2007) FLK-1-based minigene vaccines induce T cell-mediated suppression of angiogenesis and tumor protective immunity in syngeneic BALB/c mice. Vaccine 25:1409-15 |
