Overcoming DC defects in cancer patients by VEGF trap

描述（由申请人提供）：癌症免疫学的进展导致了许多肿瘤相关抗原的鉴定，这些抗原可以被人类T淋巴细胞识别并能够激活。此外，了解对T淋巴细胞活化重要的表面受体和细胞信号为更有效的癌症疫苗接种提供了许多策略。然而，这一认识伴随着令人失望的癌症患者免疫治疗的临床结果。为了对抗我们增强抗肿瘤免疫的企图，越来越多的证据表明，携带癌症的宿主发展出各种机制来抑制癌症免疫。虽然宿主免疫抑制的存在已被讨论多年，但直到最近才对其具体机制进行了更好的表征（即肿瘤抗原丢失或MHC丢失，T细胞信号传导功能障碍，APC功能障碍）。我们和其他人已经证明，在癌症患者中，免疫缺陷存在于树突状细胞（DC）谱系中，这是一种关键的抗原呈递细胞。这表现为DC成熟缺陷和来自造血祖细胞（HPC）的具有强免疫抑制作用的未成熟髓样细胞（ImC）的扩增。肿瘤细胞或宿主细胞响应肿瘤细胞而产生的VEGF是DC功能障碍的主要介质，也可能导致ImC扩增和免疫抑制。逆转这些VEGF介导的缺陷可能是有效的癌症免疫治疗的关键。

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 immunotherapy. To counter our attempts to boost anti-tumor immunity, there is a growing body of evidence that cancer-bearing hosts develop various 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. We are planning a phase I trial of intravenous VEGF Trap to be carried out at two institutions (VICC and MSKCC) in approximately 25 patients with advanced solid tumors and lymphomas. 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 protocol to this phase I trial we plan to assess changes in DC phenotype, maturation status, and 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.