In the previous funding period, we have demonstrated that: 1) Vascular Endothelial Growth Factor (VEGF), a pro-angiogenic factor produced by most human solid tumors has profound effects on hematopoiesis, specifically inhibition of Dendritic Cell (DC) differentiation and diversion of progenitors to other myeloid lineages; 2) blockade of VEGF reverses this effect in both animals and humans and significantly improves the efficacy of immunotherapy in animal models; 3) T cell differentiation is inhibited as well, inducing rapid thymic involution and diversion of lymphocytes toward B-cell differentiation, also contributing to immunosuppression; 4) VEGF-induced immunosuppression associates with dramatic expansion of immunosupressive immature myeloid cells (ImCs) capable of directly inhibiting T cell responses; 5) that treatment with retinoids promotes differentiation of these ImCs; and 6) in contrast to most known VEGF responses, VEGF receptor 1 (VEGFR1) is a major mediator of VEGF effects on immune cells and indicate involvement of tyrosine kinase-independent signaling in this process. In the next funding period, we will focus on a molecular understanding of the involved receptors and signal transduction mechanisms of VEGF effects on hematopoiesis, characterizing the effects of VEGF on T-cells and ImCs, preclinical studies of retinoids for reversial of this immunosuppression, and translation of our VEGF findings into a human therapeutic clinical trial. In our animal models we will use antibodies, specific tyrosine kinase inhibitors, and transgenic mice as molecular probes to assess the roles of both VEGF receptors and their tyrosine kinases in vivo.
We aim to screen candidate retinoids in preclinical studies of treatment targeting removal of ImCs and restoring of DC function. The clinical relevance of our findings will be tested in a phase 1/11trial co-sponsored by Cell Genesys, Inc. and CTEP combining the GVAX ?vaccine with anti-VEGF antibody in advanced non-small cell lung cancer. Our studies have thus identified and characterized a novel and significant mechanism for dysregulation of hematopoiesis leading to immunosuppression in tumor bearing hosts and the proposed studies will clarify the mechanism of this effect and directly translate our findings into therapeutic hypotheses to be tested in a human clinical trial.
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