Radiation and checkpoint blockade for cancer immune therapy

癌症免疫治疗的放射和检查点封锁

• 批准号: 10005144
• 负责人: ANDY J MINN
• 金额: $ 227.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005144
• 关键词: Advanced Malignant Neoplasm; Animal Model; Animals; Antiviral Agents; Bioinformatics; Biological Markers; Biometry; Breast Carcinoma; CTLA4 blockade; CTLA4 gene; Cellular biology; Clinical; Clinical Trials; Collaborations; Data; Dendritic Cells; Discipline; Disseminated Malignant Neoplasm; Dose; Epigenetic Process; Genetic; Genomics; Goals; Histology; Human; Immune; Immune system; Immunologics; Immunomodulators; Immunotherapy; Interferons; Investigation; Laboratories; Ligands; Local Therapy; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metastatic Melanoma; Modality; Molecular; Monoclonal Antibodies; Mus; Nature; Nivolumab; PD-1 blockade; Pancreatic carcinoma; Pathway interactions; Patients; Pattern recognition receptor; Pharmacodynamics; Phase; Preclinical Testing; Publications; RNA; Radiation; Radiation Interaction; Radiation therapy; Radiobiology; Randomized; Research; Research Personnel; Resistance; Resistance development; Role; Sampling; Schedule; Signal Transduction; Systemic Therapy; T-Lymphocyte; TNFRSF5 gene; Translating; Tumor Burden; Tumor Immunity; Untranslated RNA; cancer therapy; cancer type; data sharing; deep learning; epigenomics; exhaust; exhaustion; immune activation; immune checkpoint blockade; immunoregulation; insight; ipilimumab; irradiation; lung Carcinoma; malignant breast neoplasm; mouse model; novel; phase 2 study; phase I trial; preclinical efficacy; programmed cell death ligand 1; programmed cell death protein 1; programs; radiation effect; radiation response; randomized trial; resistance mechanism; response; success; synergism; tumor; tumor immunology

The long-term goal of this P01 is to understand the intersection of radiation biology and cancer immunology and to translate this research into better therapies with curative potential for patients with cancer. Radiation therapy (RT) can systemically impact the immune system, and recent clinical success of PD1 and CTLA4 immune checkpoint blockade (ICB) has given rise to our overarching hypothesis that the immune stimulatory effects of RT can expand the spectrum of clinical responsiveness when combined with dual ICB across multiple histologies. Our preliminary data and investigative approach bridges studies in both patients and animal models. To achieve our goals, we have developed three Projects, which require close coordination of projects and cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) nivolumab (PD1 mAb) and ipilimumab (CTLA4 mAb) with or without hypofractionated RT (HFRT) in a randomized phase II study in metastatic melanoma; and (ii) and tremelimumab (CTLA4 mAb) and durvalumab (PDL1 mAb) with HFRT at two dose schedules in metastatic pancreatic, lung, and breast carcinoma. In Project 2, we will determine the role of RT in establishing cancer immunity, evaluating the mechanism of anti-viral signaling through pattern recognition receptors and non-coding RNA and examining dendritic cell biology and CD40 activation. In Project 3, we will define the genetic and epigenetic basis of resistance to RT and ICB and examine PDL1 independent pathways to overcome this. Biomarkers revealed in Projects 2 and 3 will be examined using human samples from the clinical trials in Project 1. The Cores for this P01 are essential for our progress including provision of administration support for collaboration (Core A), a state-of-the-art platform for small animal radiation (Core B), and bioinformatics and biostatistical approaches to drive deep learning from data generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the indication of RT from “local therapy” to key part of a novel “systemic” immune therapy for meaningful efficacy against metastatic and advanced cancer.

本P01的长期目标是了解辐射生物学和癌症免疫学的交叉点 并将这项研究转化为对癌症患者具有治疗潜力的更好疗法。辐射 RT治疗可以全身性地影响免疫系统，最近PD1和CTLA4的临床成功 免疫检查点阻断（ICB）已经引起了我们的总体假设，即免疫刺激因子 当与双ICB联合使用时，RT的作用可以扩大临床反应谱， 多种组织学检查我们的初步数据和调查方法在患者和 动物模型为了实现我们的目标，我们制定了三个项目，需要密切协调， 项目和核心。在项目1中，我们将确定治疗患者的临床和免疫学影响， 两项临床试验：（i）nivolumab（PD1 mAb）和ipilimumab（CTLA 4 mAb），伴或不伴低分次RT （ii）和曲美木单抗（CTLA4 mAb），以及 在转移性胰腺癌、肺癌和乳腺癌中，durvalumab（PDL 1 mAb）联合HFRT以两种给药方案给药 carcinoma.在项目2中，我们将确定RT在建立癌症免疫中的作用，评估RT在癌症免疫中的作用。 通过模式识别受体和非编码RNA的抗病毒信号传导机制和检测 树突状细胞生物学和CD40活化。在项目3中，我们将定义遗传和表观遗传基础， 对RT和ICB的耐药性，并检查PDL 1独立途径以克服这一点。生物标志物显示， 项目2和3将使用项目1临床试验的人体样本进行检查。核心对此 P01对我们的进展至关重要，包括为合作提供行政支持（核心A）， 最先进的小动物辐射平台（核心B），以及生物信息学和生物统计学方法， 从所有项目中生成的数据驱动深度学习（核心C）。范式转变影响的潜力 是将RT的适应症从“局部治疗”转变为新的“全身”免疫治疗的关键部分， 治疗转移性和晚期癌症的有意义的疗效。