The objective of this grant application, supported by preliminary data, is to develop an anti-angiogenic treatment modality for cancer by immunization against angiogenesis associated products which are preferentially expressed during angiogenesis, anti-angiogenic immunotherapy. Murine studies will test the hypotheses that a) it is possible to stimulate an immune response against normal gene products which are preferentially, though not necessarily exclusively, expressed in the tumor vasculature; b) the immune response will negatively impact on tumor progression; c) inducing protective anti-tumor immunity targeting vasculature will not be associated with significant toxicity (autoimmunity) and d) the anti-tumor effect elicited by targeting the tumor vasculature will be synergistic with an anti-tumor immune responses targeted against the tumor. Studies will be conducted in mice immunized with mRNA tranfected dendritic cells. The proposed studies will 1) Test how powerful and general is anti-angiogenic immunotherapy, and whether combined therapy targeting endothelial products and tumor antigens, i.e., """"""""conventional"""""""" immunotherapy, has a synergistic anti-tumor effect. Transplantable as well as spontaneous tumor models will be used; 2) Mechansistc studies will evaluate the persistence of the immune response and the contribution of CD4+ and CD8+ T cell subsets. Angiogenesis measurements and immunohistochemical analysis will be used to demonstrate that the observed anti-tumor effect is caused by direct effects on the tumor vasculature: 3) Determine whether anti-angiogenic immunotherapy is associated with adverse effects resulting from impairment of normal angiogenesis. Morbidity and mortality, general pathology and specific impact on wound healing and reproduction will be analyzed. Successful conclusion of the studies proposed in this application will set the stage for human preclinical studies and clinical trials. The existence of the required expertise, infrastructure and the clinical immunotherapy programs at Duke will facilitate and expedite the clinical translation of these proof-of concept murine studies. ? ?
| Nair, Smita; Boczkowski, David; Fassnacht, Martin et al. (2007) Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67:371-80 |
| Lee, Jaewoo; Fassnacht, Martin; Nair, Smita et al. (2005) Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res 65:11156-63 |
| Fassnacht, Martin; Lee, Jaewoo; Milazzo, Caterina et al. (2005) Induction of CD4(+) and CD8(+) T-cell responses to the human stromal antigen, fibroblast activation protein: implication for cancer immunotherapy. Clin Cancer Res 11:5566-71 |
