Immune modulation of radiation therapy with Flt3 ligand

Flt3配体对放射治疗的免疫调节

• 批准号: 8566075
• 金额: $ 19.94万
• 依托单位: CELLDEX THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2013-06-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566075
• 关键词: Address; Antibodies; Antigens; Blood; Cells; Clinical Research; Dendritic Cells; Environment; Future; Hematopoietic Cell Growth Factors; Immune; Immune response; Immunity; Immunotherapy; Ligands; Localized Disease; Malignant Neoplasms; Memory; Modeling; Mus; Neoplasm Metastasis; Pathway interactions; Phenotype; Predisposition; Primary Neoplasm; Radiation therapy; Radiosurgery; Solid Neoplasm; Stem cells; T cell response; T-Lymphocyte; Tissues; Tumor Antigens; Vascular Endothelial Growth Factor Receptor-1; base; cancer therapy; immunoregulation; killings; mouse model; neoplastic cell; tumor; tumor progression

Radiation therapy (RT), specifically stereotactic radiosurgery (SRS), is frequently used in cancer treatment of localized disease. Emerging evidence provides a rationale for combining SRS with immunotherapy for treatment of incurable metastatic solid tumors. In addition to the direct killing of tumor cells, RT can cause the release of tumor antigens and molecules that promote an anti-tumor immune response. Further, RT can modify the tumor environment to increase the susceptibility of tumor cells for immune attack. We propose to combine RT with two powerful immune modulators, Fms-like tyrosine kinase ligand (Flt3L) and an antibody that activates CD27. Flt3L is a potent hematopoietic growth factor that mobilizes stem cells and greatly increases the number of dendritic cells in blood and tissues. The dendritic cells are critical for the initiation of the anti-tumor immune response. CD27 is key pathway for generating T cell immunity and memory. We will use an antibody that activates CD27 together with Flt3L to investigate the benefits of these immune modulators when combined with RT in mouse models to provide the basis for future clinical studies. By addressing the lack of immune based cancer therapies, our product offers the potential of considerable impact in reducing the toll of cancer.

放射治疗(RT)，特别是立体定向放射外科(SRS)，经常用于局部疾病的癌症治疗。新出现的证据为SRS与免疫治疗相结合治疗无法治愈的转移性实体瘤提供了理论基础。除了直接杀死肿瘤细胞外，RT还可以导致肿瘤抗原和分子的释放，从而促进抗肿瘤免疫反应。此外，RT还可以改变肿瘤环境，增加肿瘤细胞对免疫攻击的敏感性。我们建议将RT与两种强大的免疫调节剂FMS样酪氨酸激酶配体(Flt3L)和一种激活CD27的抗体相结合。Flt3L是一种强大的造血生长因子，可以动员干细胞，并极大地增加血液和组织中树突状细胞的数量。树突状细胞是启动抗肿瘤免疫反应的关键。CD27是产生T细胞免疫和记忆的关键途径。我们将使用一种能激活CD27和Flt3L的抗体来研究这些免疫调节剂在小鼠模型中与RT联合使用的好处，为未来的临床研究提供基础。通过解决缺乏基于免疫的癌症疗法，我们的产品在减少癌症死亡方面提供了相当大的影响。