Multiscale Computational Models Guided By Emerging Cellular Dynamics Quantification For Predicting Optimum Immune Checkpoint And Targeted Therapy Schedules

以新兴细胞动力学量化为指导的多尺度计算模型，用于预测最佳免疫检查点和靶向治疗方案

• 批准号: 10397586
• 负责人: Trachette Jackson
• 金额: $ 63.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397586
• 关键词: 3-Dimensional; Address; Affect; American; Antigens; Basic Science; Behavior; Biological; Biological Assay; Biological Models; Bladder Neoplasm; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Cause of Death; Cell Communication; Cells; Cessation of life; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Computational Biology; Computer Models; Cytoplasmic Granules; Data; Diagnosis; Drug Targeting; Evaluation; FDA approved; FGFR3 gene; Fibroblast Growth Factor Receptors; Future; Goals; Human; Hybrids; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunohistochemistry; Immunotherapy; Individual; Knowledge; Laboratories; Ligands; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mathematics; Measures; Mediating; Modeling; Molecular; Molecular Target; Monoclonal Antibodies; Mutation; Nivolumab; Outcome; Pathway interactions; Patient-Focused Outcomes; Persons; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Proteins; Publishing; Receptor Protein-Tyrosine Kinases; Resistance; Schedule; Speed; Survival Rate; T-Lymphocyte; Technology; Testing; Theoretical Studies; Therapeutic; Time; Translating; Treatment Failure; Treatment Protocols; Tumor Necrosis Factor Ligand Superfamily Member 6; Tyrosine Kinase Inhibitor; United States; Urinary system; Work; alternative treatment; base; cancer cell; cancer therapy; cell behavior; cell growth; cell killing; cell motility; checkpoint inhibition; checkpoint receptors; checkpoint therapy; chemotherapy; clinically relevant; computational platform; computer framework; cytotoxicity; design; experimental study; immune checkpoint; improved; in silico; information gathering; inhibitor; inhibitor therapy; innovation; insight; kinase inhibitor; live cell imaging; mathematical methods; mathematical model; movie; multi-scale modeling; neoplastic cell; novel; novel drug combination; objective response rate; programmed cell death ligand 1; receptor; response; small molecule; small molecule inhibitor; spatiotemporal; synergism; targeted agent; targeted treatment; therapeutic effectiveness; therapy design; therapy development; tool; treatment optimization; treatment strategy; tumor; tumor growth

Project Summary The principal goal of this proposal is to combine multiscale mathematical modeling with novel computational model-driven quantitative experimental platforms to develop a comprehensive and predictive 3D computational framework. Bladder cancer is one of the 10 most common cancers in the United States and in its advanced stages the 5-year survival rates are below 35%. Given the poor outcomes with chemotherapy in advanced cases, immunotherapy has emerged as an exciting domain for exploration. Monoclonal antibodies targeting the PD- 1/PD-L1 “immune checkpoint” pathway have resulted in favorable outcomes in advanced bladder cancer, and 5 drugs targeting this pathway have been approved in the past two years. Unfortunately, the objective response rates of current FDA approved immunotherapy drugs remain less than 25%. An alternative treatment strategy for bladder cancer is small molecule inhibitors (SMIs) of fibroblast growth factor receptor (FGFR3), and early clinical studies using these molecular-targeted agents have shown promise. Recently published data supporting the co-acting combination of potent immune checkpoint inhibitors and specific FGFR3 inhibitors potentially offer an advance in targeted therapeutics for cancer. A powerful and practical way to optimize novel drug combinations for clinical cancer treatment is to use sophisticated, data-driven computational models. Our proposed agent- based model platform will both aid in the characterization of tumor-immune dynamics and also suggest the best strategies for administering therapeutic combinations of immune-checkpoint and receptor kinase inhibitors. The model will be parameterized at the molecular and cellular scales by an innovative high-throughput image quantification pipeline that allows T-cell or cancer cell behaviors and interactions to be observed, tracked, and quantified. Importantly, this model system pipeline can measure the antigen burden on tumor cells and the proportion of the two types of T-cell cytotoxicity (Fas-ligand vs. granule-based). Our experimentally-driven multiscale approach is posed to (1) significantly enhance the current understanding of the impact of differential cell-kill mechanisms on tumor-immune outcomes; (2) optimize the administration of combination therapy and maximize tumor response; and (3) to improve the ability to select the most promising drugs for the clinical trials. While based on tumors of the bladder, the platform that we are developing is easily adaptable for the study of any therapy targeted to immune checkpoint proteins and receptor kinases in any tumor type. The true significance of our work lies in its translational value: our experimental and theoretical studies will be able to test clinically relevant hypotheses regarding the prospect of receptor tyrosine kinase inhibitors and immune checkpoint inhibitors to impact the mechanism of tumor cell kill by immune cells in distinct ways. Cancer is one of the leading causes of death for Americans and at present the overall effectiveness of therapeutic treatments is only approximately 50%. The development treatment optimization tools could have enormous and immediate impact on the lives of millions of people diagnosed with cancer.

项目摘要 该建议的主要目标是将多尺度数学建模与新颖的计算相结合 模型驱动的定量实验平台开发全面的、可预测的三维计算 框架。膀胱癌是美国及其晚期最常见的10种癌症之一 分期5年生存率均低于35%。鉴于晚期病例的化疗效果不佳， 免疫治疗已经成为一个令人兴奋的探索领域。针对PD的单抗- 1/PD-L1“免疫检查点”通路在晚期膀胱癌中取得了良好的疗效，5 针对这一途径的药物在过去两年中已被批准。不幸的是，客观的反应 目前FDA批准的免疫疗法药物的使用率仍然不到25%。另一种治疗策略 治疗膀胱癌的药物是成纤维细胞生长因子受体(FGFR3)的小分子抑制物(SMI)，以及早期 使用这些分子靶向药物的临床研究已经显示出希望。最近发布的数据支持 有效的免疫检查点抑制剂和特定的FGFR3抑制剂的共同作用组合可能提供 癌症靶向治疗的进展。一种强大而实用的优化新药组合的方法 用于临床癌症治疗的是使用复杂的、数据驱动的计算模型。我们推荐的代理人- 基于模型的平台将有助于肿瘤免疫动力学的表征，也将建议最好的 给予免疫检查点和受体激酶抑制剂的治疗组合的策略。这个 模型将通过创新的高通量图像在分子和细胞尺度上进行参数化 量化管道，允许观察、跟踪T细胞或癌细胞的行为和相互作用，并 量化的。重要的是，这个模型系统管道可以测量肿瘤细胞的抗原负荷和 两种类型的T细胞杀伤作用的比例(Fas配体与颗粒为基础)。我们的实验驱动 提出了多尺度方法，以(1)显著增强当前对差异影响的理解 细胞杀伤机制对肿瘤免疫结果的影响；(2)优化联合治疗和 最大限度地提高肿瘤反应；以及(3)提高选择最有希望的临床试验药物的能力。 而我们正在开发的平台以膀胱肿瘤为基础，很容易适应于肿瘤的研究 任何针对任何肿瘤类型的免疫检查点蛋白和受体激酶的治疗。真实的 我们工作的意义在于它的翻译价值：我们的实验和理论研究将能够验证 受体酪氨酸激酶抑制剂和免疫前景的临床相关假说 检查点抑制剂以不同的方式影响免疫细胞杀死肿瘤细胞的机制。癌症就是其中之一 美国人的主要死亡原因是什么？目前治疗的总体效果如何？ 大约只有50%。开发治疗优化工具可能具有巨大和立竿见影的作用 对数百万被诊断为癌症的人的生活产生了影响。