Overcoming DC defects in cancer patients by VEGF trap

通过 VEGF trap 克服癌症患者 DC 缺陷

• 批准号: 6871663
• 负责人: Jeffrey A Sosman
• 金额: $ 25.35万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-29 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871663
• 关键词: clinical research; clinical trial phase I; cytotoxic T lymphocyte; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; growth factor receptors; growth inhibitors; host organism interaction; human subject; human therapy evaluation; immunologic assay /test; leukocyte activation /transformation; leukocyte activation disorder; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; patient oriented research; tumor antigens; vascular endothelial growth factors

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.

描述（由申请人提供）：癌症免疫学的进展已导致鉴定出许多肿瘤相关抗原，这些抗原可被人T淋巴细胞识别并能够激活人T淋巴细胞。此外，了解表面受体和细胞信号对T淋巴细胞活化很重要，提示了许多更有效的癌症疫苗接种策略。然而，这一认识伴随着癌症患者免疫治疗的令人失望的临床结果。为了对抗我们增强抗肿瘤免疫力的尝试，越来越多的证据表明，癌症宿主发展了各种机制来抑制癌症免疫力。虽然宿主免疫抑制的存在已经讨论了多年，但直到最近才更好地表征了具体机制（即，肿瘤抗原丧失或MHC丧失、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，这是关键的抗原呈递细胞。这表现为DC成熟缺陷和源自造血祖细胞（HPC）的具有强效免疫抑制作用的未成熟髓样细胞（ImC）的扩增。由肿瘤细胞或宿主细胞响应于肿瘤细胞产生的VEGF是这种DC功能障碍的主要介质，并且还可能导致ImC扩增和免疫抑制。这些VEGF介导的缺陷的修复可能是有效的癌症免疫治疗的关键。 我们计划在两个机构（VICC和MSKCC）进行静脉注射VEGF Trap的I期试验，在大约25例晚期实体瘤和淋巴瘤患者中进行。VEGF Trap似乎是体内VEGF的理想抑制剂，并且提供优于受体抗体（VEGFR1和VEGFR2）或配体抗体（VEGF）或酪氨酸激酶抑制剂的优势。虽然用VEGF Trap抑制VEGF主要目的是阻断肿瘤血管生成，但它也可用于逆转对有效抗肿瘤免疫至关重要的DC功能障碍。作为该I期试验的配套方案，我们计划评估DC表型、成熟状态和功能（刺激性和ImC抑制性）的变化。VEGF Trap作为VEGF抑制的一种形式提供了克服宿主免疫抑制的方法。因此，本文所述的相关研究可能导致建立VEGF抑制，特别是VEGF Trap，作为与癌症免疫治疗联合收割机组合并增强癌症免疫治疗的方法。