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