Radiotherapy as Immunotherapy of Tumors

放射治疗作为肿瘤的免疫治疗

• 批准号: 8857115
• 负责人: SAMUEL STROBER
• 金额: $ 43.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-02 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857115
• 关键词: 4T1; Adoptive Transfer; Autologous; Blood; CD8B1 gene; CT26; Cancer Patient; Cells; Clinical Protocols; Colonic Neoplasms; Cyclophosphamide; Dendritic Cells; Disease remission; Dose; Endothelial Cells; Flow Cytometry; Future; Gene-Modified; Goals; Human; Immune; Immunity; Immunodeficient Mouse; In complete remission; Infusion procedures; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Memory; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Patients; Radiation; Radiation therapy; Regulatory T-Lymphocyte; Research Design; Role; Spleen; Staining method; Stains; Suppressor-Effector T-Lymphocytes; T cell therapy; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Tumor Immunity; base; cell motility; chemokine; chemokine receptor; chemotherapy; design; lymph nodes; macrophage; migration; neoplasm immunotherapy; neoplastic cell; pancreatic neoplasm; research study; trafficking; tumor

DESCRIPTION (provided by applicant): Our Preliminary Studies show that a single high dose of radiation or high doses of hypofractionated radiation administered to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with T cells. The T cells are required for tumor remissions. The goals of the current proposal are to determine the subsets of T cells in the spleen and lymph nodes that mediate anti-tumor immunity after transfer, and to determine whether T cells in tumors are immunodeficient and unable to transfer anti-tumor activity, and whether immune suppressor cells in the tumor can interfere with the transfer. In addition, we will determine the molecular basis of T cell migration to the tumors after radiotherapy by investigating chemokines produced by the tumors and chemokine receptors on the T cells that can infiltrate tumors. Finally, we will determine whether human pancreas tumors growing in immunodeficient mice can be induced to regress by radiation in the presence or absence of injected T cells from the tumor bearing patients. The proposed experiments use staining and flow cytometry to identify and purify immune cells for transfer studies and for analysis of tumor infiltrating cells. Gene modified mice are used to elucidate the key effector molecules used by anti-tumor T cells to mediate remissions and to traffic to tumors. The proposed studies are designed to be models for future clinical protocols that can use stereotactic body radiation (SBRT) in combination with chemotherapy and autologous T cell therapy to enhance the potency of current combinations of radiotherapy and chemotherapy to treat cancer.

描述（由申请人提供）：我们的初步研究表明，对小鼠结肠或乳腺肿瘤给予单次高剂量放射或高剂量低分割放射可诱导完全缓解以及可通过T细胞转移的全身抗肿瘤免疫。T细胞是肿瘤缓解所必需的。当前提案的目标是确定转移后介导抗肿瘤免疫的脾脏和淋巴结中的T细胞亚群，并确定肿瘤中的T细胞是否免疫缺陷而无法转移抗肿瘤活性，以及肿瘤中的免疫抑制细胞是否可以干扰转移。此外，我们将通过研究肿瘤产生的趋化因子和T细胞上可以浸润肿瘤的趋化因子受体来确定放疗后T细胞迁移到肿瘤的分子基础。最后，我们将确定在免疫缺陷小鼠中生长的人胰腺肿瘤是否可以在存在或不存在来自肿瘤携带患者的注射T细胞的情况下通过辐射诱导消退。所提出的实验使用染色和流式细胞术来鉴定和纯化免疫细胞以用于转移研究和用于肿瘤浸润细胞的分析。基因修饰的小鼠用于阐明抗肿瘤T细胞介导缓解和运输至肿瘤的关键效应分子。拟议的研究旨在成为未来临床方案的模型，这些方案可以使用立体定向体放射（SBRT）与化疗和自体T细胞治疗相结合，以增强目前放疗和化疗组合治疗癌症的效力。