Gene Expression Analysis of Dog Natural Killer Cells Following Immunotherapy with Molecularly Targeted Radionuclide therapy or Inhaled IL-15

分子靶向放射性核素治疗或吸入 IL-15 免疫治疗后狗自然杀伤细胞的基因表达分析

• 批准号: 10287107
• 负责人: Robert J. Canter
• 金额: $ 25.01万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287107
• 关键词: Activated Natural Killer Cell; Address; Animals; Antigen-Antibody Complex; Antitumor Response; Bioinformatics; Biological; Biological Assay; Biology; Blood; Canis familiaris; Cells; Clinical; Clinical Trials; Collaborations; Companions; Data; Development; Dissection; Environmental Exposure; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Goals; Growth; Heterogeneity; High-Throughput Nucleotide Sequencing; Human; Human Genome; Human Microbiome; Immune; Immune system; Immunologic Markers; Immunology; Immunooncology; Immunotherapy; Inhalation; Institution; Interdisciplinary Study; Interleukin-15; Knowledge; Light; Link; Malignant Neoplasms; Mediating; Modeling; Molecular Target; Mus; NK cell therapy; Natural Killer Cells; Oncology; Ontology; Pathway Analysis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Progressive Disease; Radioimmunotherapy; Radionuclide therapy; Reagent; Recording of previous events; Regimen; Research; Resistance; Rest; Role; Sampling; Specimen; Speed; Techniques; Testing; Time; Tissue-Specific Gene Expression; Toxic effect; Translations; Universities; Wisconsin; base; bench to bedside; cancer cell; cancer immunotherapy; clinical predictors; clinical translation; cohort; companion animal; comparative; differential expression; dog genome; genetic signature; immunotherapy trials; in vivo; neoplastic cell; novel; preclinical study; predicting response; predictive signature; responders and non-responders; response; species difference; trait; transcriptome sequencing; transcriptomics; translational impact; translational model; translational study; tumor; tumor immunology; tumor microenvironment

Project Summary Companion dogs are large, outbred animals that develop cancer spontaneously in the presence of an intact immune system, a native autochthonous tumor microenvironment, and in the setting of shared environmental exposures with humans. In fact, humans and dogs share a paired evolutionary history which has led to greater similarities between canine and human genomes and microbiomes than between mouse and human. Together, these traits make dogs an advantageous translational model to study cancer immunology and cancer immunotherapy, and dog clinical trials allow for the study of complex immune interactions during therapy while also addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires the development of robust and validated assays and reagents, and a deeper understanding of dog immunology and immune biomarkers is necessary to achieve high impact translational studies, especially in the context of natural killer (NK) cells where significant species differences are known to exist. This proposal will build on exciting data from the collaborating institutions with significant expertise in comparative oncology and novel immunotherapy trials underway. Using pre- and on-treatment PBMC samples from dogs on trial receiving novel and “first-in-class” immunotherapies which stimulate NK cells, we will use RNA sequencing to examine NK differential gene expression to 1) establish robust and validated gene signatures of resting and activated dog NK cells from both clinical trial cohorts; 2) analyze NK gene signatures from responding and non-responding patients; and 3) evaluate for similarities and differences in NK gene signatures between respective NK stimulatory immunotherapies which are anticipated to have overlapping, but distinct, mechanisms of action. Results from this proposal will extend the important link that canine studies provide between murine pre-clinical studies and human clinical trials and facilitate the rapid translation of novel, potentially high impact NK therapies to both dog and human patients with aggressive cancers.

项目摘要 伴侣犬是大型的杂种动物，在存在下自发发展癌症 完整的免疫系统，天然自我肿瘤微环境，并在环境中 与人类的共同环境暴露。实际上，人类和狗有一对 进化史导致犬与人类基因组之间的相似之处更大 和微生物组比小鼠和人之间。这些特征在一起使狗成为 研究癌症免疫学和癌症免疫疗法的有利翻译模型，以及 狗的临床试验允许研究治疗过程中复杂的免疫相互作用 解决癌症免疫疗法的长期效率和毒性。但是，免疫 解剖需要开发可靠和经过验证的测定法和试剂，并更深入 对狗免疫学和免疫生物标志物的理解对于实现高影响力是必要的 翻译研究，尤其是在自然杀手（NK）细胞的背景下 已知物种差异存在。该提案将以令人兴奋的数据为基础 与比较肿瘤学和新颖的重要专家合作的机构 正在进行免疫疗法试验。使用试验中的狗的预处理和治疗PBMC样品 接收刺激NK细胞的小说和“一流”免疫疗法，我们将使用RNA 测序以检查NK差异基因表达至1）建立健壮并验证 来自两个临床试验队列的休息和活化狗NK细胞的基因特征； 2）分析 来自反应和无反应患者的NK基因信号； 3）评估 相对NK刺激之间NK基因特征的相似性和差异 预计会有重叠但独特的作用机理的免疫疗法。 该提案的结果将扩展犬研究提供的重要链接 鼠前研究和人类临床试验，并促进新颖的快速翻译， 对患有侵略性癌症的狗和人类患者的潜在高影响NK疗法。

项目成果

Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.

• DOI: 10.7150/thno.54881
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Jagodinsky JC;Jin WJ;Bates AM;Hernandez R;Grudzinski JJ;Marsh IR;Chakravarty I;Arthur IS;Zangl LM;Brown RJ;Nystuen EJ;Emma SE;Kerr C;Carlson PM;Sriramaneni RN;Engle JW;Aluicio-Sarduy E;Barnhart TE;Le T;Kim K;Bednarz BP;Weichert JP;Patel RB;Morris ZS
• 通讯作者: Morris ZS

MRI-Guided Radiation Therapy.

• DOI: 10.1016/j.yao.2021.02.003
• 发表时间: 2021-05
• 期刊: Advances in oncology
• 作者: S. Lee;W. Hall;Z. Morris;Leslie Christensen;M. Bassetti

Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.

• DOI: 10.1371/journal.pone.0255798
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Magee K;Marsh IR;Turek MM;Grudzinski J;Aluicio-Sarduy E;Engle JW;Kurzman ID;Zuleger CL;Oseid EA;Jaskowiak C;Albertini MR;Esbona K;Bednarz B;Sondel PM;Weichert JP;Morris ZS;Hernandez R;Vail DM
• 通讯作者: Vail DM