In order to achieve maximal antitumor immunity that leads to sustainable tumor regression, breast cancer patients are often treated with a combination of therapeutic modalities consisting of chemotherapy and/or radiation therapy supplemented with a more targeted immunotherapeutic approach. Herein, we propose to test the therapeutic efficacy of a combinatorial therapy that joins the immunostimulatory effects of cytokines and Toll-like receptor (TLR) agonists with the cytotoxic potency of the promising anticancer drug Ukrain (NSC 631570). Preliminary studies indicate that following vaccination with tumor membranes expressing membrane-anchored IL-12 that partial tumor regression can be achieved. Additionally, we have shown the potent in vitro cytotoxicity of Ukrain on 4T07 mouse tumor cells, our proposed breast cancer model. While these membrane-based vaccines expressing membrane-anchored immunostimulatory molecules will primarily target immune cells of the adaptive immune response, the simultaneous vaccination with the TLR- ligands, monophosphoryl lipid A (MPL) and unmethylated CpG-motifs (CpG), will activate innate immune cells, most notably DCs that will further augment the overall antitumor response. Additionally, Ukrain, which exhibits cytostatic and cytolytic activity against several human cancer cell lines including colon, brain, ovarian, melanoma and lymphoma without adverse harmful side effects on healthy human cells {2917-2920}, has also been shown to exhibit immune modulatory functions, namely by increasing the number of cytotoxic T cells while decreasing the number of suppressor T cells {2918}. With the addition of Ukrain as part of the vaccination regime, the overall tumor burden is likely to be reduced which will further enhance the degree and longevity of immune responses induced following vaccination. The knowledge gained from these studies will identify an effective combination of a membrane- based vaccine and immunological adjuvants that is likely to form a solid foundation for designing vaccine formulations to treat breast cancer in humans.
I propose to develop a therapeutic cancer vaccine that will elicit robust antitumor immune responses capable of inducing significant and sustainable tumor regression. The research proposed will identify an effective combination of a membrane-based vaccine and immunological adjuvants that is likely to form a solid foundation for designing vaccine formulations to treat breast cancer in patients.
