I.VEGF receptor 2 (R2) is expressed mainly on proliferating endothelial cells, and plays an important role in tumor growth and metastasis. Thus, developing a CTL response might inhibit tumor angiogenesis. Therefore, we have identified several MHC Class I binding sequences from murine and human VEGF R2. We found that these peptides exhibit high binding affinity to HLA-A2, can induce specific T cell activation measured by IFN-gamma production and CTL able to lyse VEGF R2 expressing cells lines, and can eliminate endothelial cells expressing the VEGF R2 in an animal tumor model and decrease tumor growth. This work was published in 06. 2. we are building on the above discoveries to test the combination of anti angiogenesis vaccines combined with small molecules also targeting different targets in the angiogenesis process such as Gleevec which selectively inhibits ABL tyrosine kinase, PDGFR and c-kit. accordingly we are testing whether there is synergistic effect on inhibiting solid tumor growth when combining anti angiogenesis agent and peptide vaccine. 3. We further built on that by developing an enhanced strategy for utilizing whole endothelial cell line modified with an immune enhancing molecule LIGHT. We found that by utilizing these endothelial cell lines expressing the LIGHT protein that we generate specific immune response against endothelial cells which lead to the inhibition of angiogenesis. Furthermore, we found that this strategy can inhibit the growth of melanoma tumor. This manuscript is finalized and will be submitted for publication. Currently, we are also testing the combination of anti endothelial vaccine approach with small molecules targeting the tyrosine kinase moiety of the VEGFR2 receptor. 4. Finally, we are working on discovering other angiogenesis antigens taking the approach of testing genes that are differentially expressed in tumor endothelial tumors in comparison to normal endothelial cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Mkrtichyan, Mikayel; Najjar, Yana G; Raulfs, Estella C et al. (2012) B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets. J Immunol 189:2338-47
Meyskens Jr, Frank L; Curt, Gregory A; Brenner, Dean E et al. (2011) Regulatory approval of cancer risk-reducing (chemopreventive) drugs: moving what we have learned into the clinic. Cancer Prev Res (Phila) 4:311-23
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Mkrtichyan, Mikayel; Najjar, Yana G; Raulfs, Estella C et al. (2011) Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Eur J Immunol 41:2977-86