Radiotherapy as Immunotherapy of Tumors

放射治疗作为肿瘤的免疫治疗

基本信息

批准号：
8370487
负责人：
SAMUEL STROBER
金额：
$ 43.79万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-02 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8370487
关键词：
Adoptive Transfer Autologous Blood CD8B1 gene 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 Immunotherapy 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 neoplastic cell pancreatic neoplasm research study trafficking tumor

项目摘要

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. PUBLIC HEALTH RELEVANCE: Our Preliminary Studies showed that a single high of radiation to colon or breast tumors in mice can induce complete remissions as well as systemic anti-tumor immunity that is transferable with immune cells called T cells. The T cells are required for remissions. The proposed studies will determine the types of T cells that induce remissions, whether tumors contain cells that can suppress the transfer of anti-tumor activity, and whether human pancreas cancers growing in mice can be induced to regress in the presence or absence of injected T cells from the cancer patients.

描述（由申请人提供）：我们的初步研究表明，对小鼠的结肠或乳腺肿瘤施用的单一高剂量的辐射或高剂量的降低辐射可以诱导完全缓解，以及可转移T细胞的全身性抗肿瘤免疫。 T细胞是肿瘤缓解所必需的。当前建议的目标是确定脾细胞和转移后介导抗肿瘤免疫力的淋巴结中的T细胞子集，并确定肿瘤中的T细胞是否是免疫缺陷且无法转移抗肿瘤活性的，以及肿瘤中的免疫抑制细胞是否可以接触转移。此外，我们将通过研究可以浸润肿瘤的T细胞上的肿瘤和趋化因子受体产生的趋化因子来确定放疗后T细胞迁移到肿瘤的分子基础。最后，我们将确定在存在或不存在来自肿瘤患者肿瘤患者的注射的T细胞的情况下，在免疫缺陷小鼠中生长的人胰腺肿瘤是否可以通过辐射降低。提出的实验使用染色和流式细胞仪来识别和纯化免疫细胞进行转移研究和分析肿瘤浸润细胞。基因改性小鼠用于阐明抗肿瘤T细胞使用的关键效应分子，以介导减轻和肿瘤。拟议的研究旨在成为未来临床方案的模型，可以将立体定向的身体辐射（SBRT）与化学疗法和自体T细胞疗法结合使用，以增强放射疗法和化学疗法当前组合的效力来治疗癌症。公共卫生相关性：我们的初步研究表明，小鼠中对结肠或乳腺肿瘤的单个辐射可以诱导完全缓解，以及可通过称为T细胞的免疫细胞转移的全身抗肿瘤免疫。 T细胞是必需的。拟议的研究将确定诱导缓解的T细胞的类型，肿瘤是否包含可以抑制抗肿瘤活性转移的细胞，以及在存在或不存在癌症患者注射的T细胞的情况下，在小鼠中生长的人类胰腺癌是否可以诱导回归。