Advancing immunotherapy through cross species studies of immune cell responses and immune checkpoint inhibitor effects in dogs and humans with invasive urinary bladder cancer

通过对患有侵袭性膀胱癌的狗和人类的免疫细胞反应和免疫检查点抑制剂作用的跨物种研究来推进免疫治疗

• 批准号: 10651879
• 负责人: DEBORAH W KNAPP
• 金额: $ 55.25万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651879
• 关键词: Address; Advanced Malignant Neoplasm; Adverse event; Affect; Animal Cancer Model; Animal Model; Behavior; Bioinformatics; Cancer Model; Canis familiaris; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Clinic; Clinical; Clinical Data; Clinical Trials; Complement; Data; Data Commons; Data Set; Deposition; Disease; Disease remission; Drug Kinetics; Experimental Models; FDA approved; Failure; Genomics; Goals; Health; Health Care Costs; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunobiology; Immunology; Immunotherapy; Invaded; Literature; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Medical Oncology; MicroRNAs; Minority; Mission; Modeling; Molecular; NCI Center for Cancer Research; Nature; Neoplasm Metastasis; Outcome; Pathologic; Pathology; Patients; Persons; Prediction of Response to Therapy; Public Health; Publishing; RNA analysis; Reporting; Research; Safety; Sampling; TYRO3 gene; Transitional Cell Carcinoma; United States; United States National Institutes of Health; Universities; Work; anti-PD-L1 antibodies; cancer heterogeneity; cancer immunotherapy; canine model; checkpoint therapy; comparative; improved; microbiome research; molecular subtypes; neoplastic cell; outcome prediction; pre-clinical; prevent; programmed cell death protein 1; response; single-cell RNA sequencing; success; transcriptome sequencing; treatment response; tumor; tumor microenvironment

Project Summary / Abstract Invasive urinary bladder cancer (invasive urothelial carcinoma, InvUC) is lethal in 50% of patients. Immune checkpoint inhibitors (ICIs) can cause dramatic remission of advanced InvUC, but only ~20% of patients have this level of benefit. Pre-clinical animal models are critical for research to improve ICI outcomes, but experimental models lack many of the hallmark features of human cancer and are poor predictors of outcomes in humans. To address the gap in relevant animal cancer models for immunotherapy research, we will study dogs with naturally-occurring InvUC as canine InvUC closely mimics the human condition in pathology, molecular features including luminal and basal subtypes, clinical presentation, local invasion, and frequent metastasis. The proposed work will strengthen the canine InvUC model by defining immune cell responsiveness and ICI outcomes, with comparison to human studies. Our long range goal is to improve the outlook for people with InvUC. The objective of this proposal is to address the gap by determining the suitability of canine InvUC to serve as a model to improve ICI therapy in humans. The central hypothesis is marked similarities will exist between dogs and humans in the immune cell responses in InvUC, and ICI therapy effects including immune adverse events, antitumor activity, immunological responses, and predictors of treatment success and failure. Some differences between dogs and humans are expected, with these also being informative. The hypothesis is formulated and based on strong evidence in the literature and preliminary data. The rationale is that demonstrating the shared immune cell responses and ICI effects between dogs and humans with InvUC will allow the canine model to be fully employed to improve ICI therapy for humans. The objective will be accomplished through two specific aims: (1) determine similarities and differences between dogs and humans in the immune cell responsiveness to InvUC, and (2) determine the safety and antitumor activity of a canine PD-L1 antibody and predictors of success and failure in dogs with InvUC with comparison to findings in humans. The approach will be to: (1) perform dog-human comparison of InvUC through analyses of RNA-seq, scRNA-seq, WGS, and CITE-seq data, and (2) conduct a clinical trial of an ICI, our canine PD-L1 antibody, in dogs with InvUC to assess antitumor activity, pharmacokinetics, adverse event profile, and correlative sequencing and clinical data to predict outcomes, and to compare results to those from human PD- L1 antibody trials. The expected results will define shared immune cell responses and ICI effects in dogs and humans, expand the understanding of predictors of ICI therapy, and justify use of the canine model to improve ICI and other immunotherapies in humans. Samples from dogs in the ICI trial will also be made available for other immune, microRNA, and microbiome research by our collaborators and beyond. We look forward to contributing to the Canine Cancer Immunotherapy Network and depositing our study data in the NCI's Integrated Canine Data Commons, to complement two InvUC data sets that we have previously deposited.

项目摘要 /摘要 在50％的患者中，浸润性膀胱癌（浸润性尿路上皮癌，Invuc）致命。免疫 检查点抑制剂（ICIS）可能会导致晚期INVUC的急剧缓解，但只有约20％的患者患有 这种利益水平。临床前动物模型对于改善ICI结果的研究至关重要，但是 实验模型缺乏人类癌症的许多标志性特征，并且是结果的不良预测指标 在人类中。为了解决有关免疫疗法研究相关动物癌模型中的差距，我们将研究 犬类自然出现时，犬的狗可以紧密地模仿病理学中的人类状况， 分子特征，包括腔内和基础亚型，临床表现，局部侵袭以及频繁 转移。拟议的工作将通过定义免疫细胞来增强犬类Invuc模型 与人类研究相比，响应能力和ICI结果。我们的远距离目标是改善 患有Invuc的人的前景。该提议的目的是通过确定适用性来解决差距 犬的象征是改善人类ICI疗法的模型。中央假设被标记 狗和人之间的相似之处在INVUC中的免疫细胞反应中，ICI治疗效果将存在相似之处 包括免疫不良事件，抗肿瘤活性，免疫反应和治疗预测指标 成功与失败。狗和人之间的某些差异是可以的，而这些也是 内容丰富。该假设是由文献和初步数据中的有力证据提出的。 理由是证明狗之间的共享免疫细胞反应和ICI影响 具有Invuc的人将允许犬模型完全使用以改善人类的ICI疗法。这 目标将通过两个具体目标来实现：（1）确定相似性和差异 免疫细胞对Invuc的反应性的狗和人类，以及（2）确定安全性和抗肿瘤 犬PD-L1抗体的活性以及与比较的狗的成功和失败的预测指标 在人类中的发现。该方法将是：（1）通过分析对Invuc进行狗 - 人类的比较 RNA-seq，Scrna-Seq，WGS和Cite-Seq数据，以及（2）进行ICI的临床试验，我们的犬PD-L1 抗体，在具有抗肿瘤的狗中评估抗肿瘤活性，药代动力学，不良事件特征和 相关测序和临床数据以预测结果，并将结果与​​人类PD的结果进行比较 L1抗体试验。预期的结果将定义狗的共享免疫细胞反应和ICI效应，以及 人类，扩大对ICI治疗预测因素的理解，并证明使用犬模型来改进 ICI和其他人类免疫疗法。 ICI试验中的狗的样本也将用于 我们的合作者及其他地区的其他免疫，microRNA和微生物组研究。我们期待 为犬类癌免疫疗法网络做出贡献，并将我们的研究数据存储在NCI的 集成的犬类数据共享，以补充我们先前存放的两个Invuc数据集。