Mechanistic basis of allogeneic IgG-induced tumor eradication

同种异体IgG诱导肿瘤根除的机制基础

基本信息

批准号：
9089595
负责人：
Ian Lisle Linde
金额：
$ 4.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089595
关键词：
Adoptive Transfer Alloantigen Allogenic Antibodies Antigen Targeting Antigens Autoantigens Autologous Automobile Driving Binding Binding Proteins Biological Biological Assay Biology Breast Carcinoma CD8B1 gene Cells Clinic Cloud Computing Common Neoplasm Data Dendritic Cells Dendritic cell activation Distant Drug or chemical Tissue Distribution Fluorescence Foundations Future Genetic Engineering Genetically Engineered Mouse Goals Health Human Immune Immune system Immunity Immunoglobulin G Immunotherapeutic agent In Vitro Injection of therapeutic agent Knowledge Lymphoid Malignant Neoplasms Manuscripts Mass Spectrum Analysis Mediating Membrane Proteins Methods Modeling Monoclonal Antibodies Mus Mutate Nature Neoplasm Metastasis Normal Cell Normal tissue morphology Organ Pancreatic carcinoma Phenotype Primary Neoplasm Process Proteomics Recombinant Proteins Resected Sampling Specificity Staining method Stains Stimulus T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Tissues Toxic effect Translating Translations Transplantation Tumor Antigens Tumor Immunity antigen binding base cDNA Library cancer immunotherapy combinatorial in vivo insight lung Carcinoma melanoma mouse model neoplastic cell novel novel therapeutics response screening tumor tumor eradication uptake

项目摘要

DESCRIPTION (provided by applicant): Despite the ability of the adaptive immune system to distinguish subtle differences between self and non-self antigens, cancers grow and disseminate in their hosts. Using models of allogeneic tumors, which, like transplanted allogeneic organs and tissues, are rejected by the host's adaptive immune system, it was discovered that naturally-occurring IgG antibodies initiate allogeneic tumor rejection. Applying these findings to syngeneic and autologous tumors, allogeneic IgG, when applied in the proper stimulatory context, has been shown to be capable of driving dendritic cell uptake of tumor antigens and systemic T cell-mediated eradication of both primary tumors and distant untreated tumors and metastases, and key aspects of this mechanism have been demonstrated to be conserved in humans. These data represent a promising new cancer immunotherapeutic approach. The objectives of this project are to develop a detailed understanding of the mechanisms responsible for the capacity of naturally occurring tumor-binding allogeneic IgG to eradicate tumors. The hypothesis is that allogeneic IgG and the elicited T cells do not recognize the same antigens, and that while any antibody that binds tumor cells at sufficient levels is capable of activating dendritic cell-mediated T cell immunity, the T cell response converges upon common tumor antigens sufficient to drive tumor eradication. Thus, utilizing mouse models of melanoma, the aims of this project are twofold: 1) to determine the identity and tissue distribution of the melanoma antigens recognized by allogeneic IgG, and 2) to analyze the specificity, phenotype, and function of T cells elicited by allogeneic IgG therapy. Toward these ends, the antigens bound by allogeneic IgG will be identified by mass spectrometry proteomic approaches, assessed for expression on normal tissues, and therapeutically targeted with monoclonal antibodies. Similarly, the T cell clones elicited by allogeneic IgG therapy will be assessed with a statistical framework utilizing combinatorial sampling and cloud computing to determine convergent groups of clones recognizing common antigens, screened to identify the antigens recognized, studied to determine in vivo phenotype, and tested for anti-tumor function. These studies will provide a detailed understanding of the mechanism of allogeneic IgG therapy, establishing a foundation of knowledge to inform future efforts to translate allogeneic IgG therapy to the clinic, and they will also provide biological insight into the systemic coordinationof tumor-specific T cells during a tumor-eradicating response.

描述（由适用提供）：尽管自适应免疫系统能够区分自我和非自身抗原之间的细微差异，但癌症仍在其宿主中生长和传播。使用同种异体肿瘤的模型，这些模型像移植的同种异体器官和组织一样被宿主的适应性免疫系统拒绝，发现自然存在的IgG抗体会引发同种异体肿瘤的排斥。将这些发现应用于合成性和自体肿瘤，同种异体IgG在适当的刺激环境中应用，已被证明能够驱动肿瘤抗原的树突状细胞摄取以及全身性T细胞介导的原发性肿瘤的放射线，远距离的原代肿瘤和未经培训的肿瘤和转移的肿瘤和转移和转移和钥匙的态度已被证明是在这种机械方面被证明。这些数据代表了一种有希望的新癌症免疫治疗方法。该项目的目标是对负责自然存在的肿瘤结合同种异体IgG对放射性肿瘤的能力的机制进行详细的理解。假设是同种异体IgG和引起的T细胞不识别相同的抗原，尽管任何在足够水平上结合肿瘤细胞的抗体都能够激活树突状细胞介导的T细胞免疫，但T细胞反应在足以驱动肿瘤的常见肿瘤抗原上会逆转T细胞反应。这是使用黑色素瘤的小鼠模型，该项目的目的是双重的：1）确定同种异体IgG识别的黑色素瘤抗原的身份和组织分布，以及2）分析由同种异体IgG治疗引起的T细胞的特异性，表型和功能。朝向这些目的，通过质谱法蛋白质组学方法将鉴定受同种异体IgG绑定的抗原，并评估在正常时机上的表达，并以单克隆抗体的治疗靶向。同样，将使用组合采样和云计算的统计框架来评估同种异体IgG治疗引起的T细胞克隆，以确定克隆的收敛基团识别常见的抗原，筛选以识别已识别的抗原，suttoiod，studiod，以确定在体内表型，并测试了抗肿瘤功能的抗原。这些研究将对同种异体IgG疗法的机制提供详细的理解，并为未来的努力提供了知识的基础，以将同种异体IgG疗法转化为诊所，并且它们还将在肿瘤疗法的反应期间对肿瘤特异性T细胞的系统性协调提供生物学见解。