Visualizing radiation-induced tumor immune responses

可视化辐射诱导的肿瘤免疫反应

• 批准号: 9908059
• 负责人: Dorthe Schaue
• 金额: $ 21.71万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908059
• 关键词: Address; Adjuvant; Affinity; Antibodies; Apoptosis; Binding; Biological; Biological Markers; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; CT26; Cell Death; Cell Death Induction; Cell surface; Cells; Cessation of life; Clinic; Clinical; Clinical Research; Combination immunotherapy; Complex; Cytotoxic Chemotherapy; Dendritic Cells; Detection; Development; Disease; Dose; Dose Fractionation; Effector Cell; Enzyme-Linked Immunosorbent Assay; Evaluation; Flow Cytometry; Frustration; Goals; Human; Image; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; ImmunoPET; Immunoglobulin Fragments; Immunologic Monitoring; Immunotherapy; Inbred BALB C Mice; Inbred C3H Mice; Infiltration; Innate Immune System; Label; Lead; Licensing; Malignant Neoplasms; Measures; Medicine; Modality; Monitor; Mus; Nature; Necrosis; Normal tissue morphology; Operative Surgical Procedures; Pathway interactions; Phage Display; Play; Positioning Attribute; Positron-Emission Tomography; Public Health; Radiation; Radiation therapy; Radiolabeled; Recombinants; Research Personnel; Schedule; Scientist; Signal Transduction; Solid; Spleen; T cell response; T cell therapy; Time; Tissues; Toxic effect; Translating; Tumor-infiltrating immune cells; Uncertainty; Work; antibody engineering; antibody libraries; arm; calreticulin; cancer immunotherapy; cancer therapy; checkpoint therapy; chemotherapy; cross reactivity; cytotoxic; cytotoxic CD8 T cells; early detection biomarkers; experience; fighting; fractionated radiation; imaging probe; immune checkpoint blockade; immunogenic; immunogenic cell death; immunoreactivity; in vivo; in vivo Model; innovation; irradiation; lymph nodes; microPET; mouse model; nanomolar; neoplastic cell; non-invasive imaging; novel; pathogen; predictive marker; response; side effect; success; tool; tumor; tumor growth

PROJECT SUMMARY / ABSTRACT There is no doubt that the remarkable success of checkpoint blockade and of adoptive T cell transfer in the clinic has positioned immunotherapy firmly as the fourth pillar of cancer treatment, next to surgery, radiotherapy, and chemotherapy and created opportunities and challenges in equal measures. Some of the most pressing questions we are facing include 1) relatively limited response rates, 2) the emergence of immune-related side effects, and 3) a lack of predictive biomarkers. While combining immunotherapies, within and across modalities will address some of these challenges, new ones are likely to arise. Certainly, radiation therapy combined with immunotherapy can yield promising responses, but our understanding of the mechanisms involved is very limited. Perhaps the most compelling aspect of radiation therapy lies in its cytotoxic nature and its ability to create a hub of immunogenic tumor cell death which is characterized by a unique biomarker signature, most notably cell surface exposure of calreticulin. Dendritic cells have the exceptional ability to sense danger signals and relay them to the adaptive arm of the immune system by way of licensing cytotoxic CD8 T to seek out their target and kill. The important issue is to understand when this happens, when it doesn't happen and if it translates into systemic immunity and the ability to fight micrometastatic disease. However, our tools to address these questions are totally inadequate. Indeed, this proposal aims to develop powerful new tools that allow us to interrogate the tumor-host interface by noninvasively imaging immune cells during an active immune response using engineered antibody fragments and immunoPET. A novel calreticulin immunoPET probe will be developed, and evaluated alongside an existing CD8 immunoPET probe for the ability to assess the induction of immunogenic cell death and the influx and expansion of effector cells. The goal is to demonstrate that CD8 immunoPET can be used to monitor tumor immune responses during radiation therapy; that calreticulin immunoPET can provide an early non- invasive biomarker of immunogenic cell death and predict subsequent CD8 T cell infiltration in tumors, and that the combination of calreticulin and CD8 imaging can be used to optimize RT dose/fractionation schedules so as to create the optimal adjuvant to immunotherapy.

项目概要/摘要 毫无疑问，检查点封锁和过继性 T 细胞转移在 诊所将免疫疗法牢牢定位为仅次于手术的癌症治疗第四支柱， 放疗、化疗，既带来了机遇，也带来了挑战。一些 我们面临的最紧迫的问题包括 1) 答复率相对有限，2) 免疫相关副作用，3) 缺乏预测性生物标志物。在联合免疫疗法的同时， 跨模式将解决其中一些挑战，但可能会出现新的挑战。当然，辐射 与免疫疗法相结合的疗法可以产生有希望的反应，但我们对 涉及的机制非常有限。也许放射治疗最引人注目的方面在于它 细胞毒性性质及其创建免疫原性肿瘤细胞死亡中心的能力，其特征是 独特的生物标志物特征，最显着的是细胞表面暴露的钙网蛋白。树突状细胞具有 感知危险信号并将其传递给免疫系统适应性臂的特殊能力 许可细胞毒性 CD8 T 寻找目标并杀死它们。重要的问题是要理解什么时候 发生、不发生以及是否转化为系统免疫力和抵抗能力 微转移性疾病。然而，我们解决这些问题的工具完全不够。确实，这 该提案旨在开发强大的新工具，使我们能够通过以下方式询问肿瘤-宿主界面： 使用工程抗体片段在主动免疫反应期间对免疫细胞进行无创成像 和免疫PET。将开发一种新型钙网蛋白免疫 PET 探针，并与 现有的 CD8 免疫 PET 探针能够评估免疫原性细胞死亡的诱导以及 效应细胞的流入和扩增。目标是证明 CD8immunoPET 可用于监测 放射治疗期间的肿瘤免疫反应；钙网蛋白免疫PET可以提供早期非 免疫原性细胞死亡的侵入性生物标志物并预测随后的肿瘤中 CD8 T 细胞浸润 钙网蛋白和 CD8 成像的组合可用于优化 RT 剂量/分割方案，以便 从而创造免疫疗法的最佳佐剂。