Overcoming DC defects in cancer patients by VEGF trap

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DESCRIPTION (provided by applicant): Progress in cancer immunology has led to the identification of numerous tumor-associated antigens that are recognized by and able to activate human T lymphocytes. Furthermore, understanding the surface receptors and cellular signals important to T lymphocyte activation suggests numerous strategies for more effective cancer vaccination. Nevertheless, this knowledge is accompanied by disappointing clinical results in cancer patients with active specific immunotherapy. To counter our attempts to boost anti-tumor immunity, there is a growing body of evidence that cancer-bearing hosts develop a number of mechanisms to suppress cancer immunity. While the presence of host immunosuppression has been discussed for many years, only recently have the specific mechanisms been better characterized (i.e., tumor antigen loss or MHC loss, T cell signaling dysfunction, APC dysfunction). We and others have demonstrated that in cancer patients, immune defects are present in the dendritic cell (DC) lineage, the critical antigen-presenting cell. This is manifested by defects in DC maturation and an expansion of immature myeloid cells (ImC) with potent immunosuppressive effects that are derived from hematopoietic progenitor cells (HPC). VEGF produced by tumor cells or host cells in response to tumor cells is a major mediator of this DC dysfunction and may also lead to ImC expansion and immunosuppression. Reversal of these VEGF mediated defects may be critical to effective cancer immunotherapy. A multi-institutional phase I trial of intravenous VEGF Trap in approximately 25 patients with advanced solid tumors and lymphomas is being planned under Regeneron. VEGF Trap appears to be an ideal inhibitor of VEGF in vivo and offers advantages over antibody to receptor (VEGFR1 and VEGFR2) or to ligand (VEGF) or tyrosine kinase inhibitors. While VEGF inhibition with VEGF Trap is primarily aimed at blocking tumor angiogenesis, it may also act to reverse DC dysfunction critical to effective anti-tumor immunity. As a companion correlative study to this phase I trial we plan to assess changes in DC phenotype, maturation status, and their function (stimulatory and ImC inhibitory). VEGF Trap as a form of VEGF inhibition provides an approach to overcome host immunosuppression. Thereby, the correlative studies described here may lead to the establishment of VEGF inhibition, VEGF Trap, specifically, as an approach to combine with and enhance cancer immunotherapy.