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 浸润性膀胱癌(浸润性尿路上皮癌，InvUC)在50%的患者中是致命的。免疫 检查点抑制物(ICIS)可导致晚期InvUC显著缓解，但仅有~20%的患者 这种程度的好处。临床前动物模型对于改善ICI预后的研究至关重要，但 实验模型缺乏人类癌症的许多标志性特征，并且不能很好地预测结果 在人类身上。为了解决相关动物癌症模型在免疫治疗研究中的差距，我们将研究 带有自然产生的InvUC的狗与犬的InvUC在病理上非常接近人类的情况， 分子特征包括管腔和基础亚型、临床表现、局部侵袭和频繁 转移。这项拟议的工作将通过定义免疫细胞来加强犬的InvUC模型 反应性和ICI结果，与人体研究相比较。我们的长期目标是改善 对InvUC患者的展望。这项建议的目标是通过确定是否合适来解决差距。 作为改进人类ICI治疗的模型。中心假说被标记为 犬和人之间在免疫细胞反应和ICI治疗效果方面存在相似之处 包括免疫不良事件、抗肿瘤活性、免疫反应和治疗预测因素 有成功也有失败。狗和人之间的一些差异是可以预料的，这些也是 见多识广。这一假设是建立在强有力的文献证据和初步数据的基础上的。 其基本原理是，展示狗和狗之间共享的免疫细胞反应和ICI效应 患有InvUC的人类将允许充分利用犬类模型来改进人类的ICI治疗。这个 目标将通过两个具体目标来实现：(1)确定 犬和人的免疫细胞对InvUC的反应性，以及(2)确定其安全性和抗肿瘤作用 犬PD-L1抗体的活性与犬非溃疡性结肠炎成败的预测指标比较 在人类身上的发现。方法是：(1)通过分析，对InvUC进行狗-人比较 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，用于评估InvUC的抗肿瘤活性、药代动力学、不良事件描述和 相关测序和临床数据以预测结果，并将结果与人类PD- L1抗体试验。预期的结果将定义狗的共同免疫细胞反应和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善 ICI和其他人类免疫疗法。ICI试验中的犬只样本也将用于 我们的合作者和其他人进行的其他免疫、microRNA和微生物组研究。我们期待着 向犬癌免疫治疗网络捐款，并将我们的研究数据存储在NCI的 集成的犬类数据共享空间，以补充我们之前存储的两个InvUC数据集。