Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis

利用睡美人诱变合理改进 T 细胞介导的免疫治疗

• 批准号: 9503289
• 负责人: Laura Marie Rogers
• 金额: $ 18.58万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9503289
• 关键词: Address; Adoptive Transfer; Applications Grants; Bioinformatics; Cancer Immunology Science; Cancer Model; Cancer Patient; Candidate Disease Gene; Doctor of Philosophy; Environment; Faculty; Foundations; Funding; Genes; Genetic Screening; Goals; Holden Comprehensive Cancer Center at the University of Iowa; Immune; Immunocompetent; Immunotherapeutic agent; Immunotherapy; Institution; Interdisciplinary Study; Iowa; K22 Award; Knock-out; Lead; Lymphoma; Mediating; Mentors; Modeling; Mus; Mutagenesis; Mutate; Mutation; Patients; Positioning Attribute; Pre-Clinical Model; Prevalence; Process; Research; Research Personnel; Series; Sleeping Beauty; System; Systems Biology; T cell therapy; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Training; Tumor-infiltrating immune cells; Universities; Work; anti-PD-1; anti-PD1 therapy; antitumor effect; base; cancer immunotherapy; cancer therapy; cancer type; career; chimeric antigen receptor T cells; cohort; design; experience; experimental study; gene discovery; immune checkpoint blockade; improved; innovation; interest; loss of function mutation; melanoma; mouse model; novel; novel strategies; novel therapeutics; overexpression; patient population; programs; public health relevance; screening; skills; small hairpin RNA; success; tenure track; therapeutic gene; therapeutic target; treatment strategy; tumor; tumor microenvironment; whole genome

Project Summary/Abstract I, Dr. Laura Rogers, PhD, am currently a mentored postdoctoral researcher at the University of Iowa Holden Comprehensive Cancer Center. I intend to pursue an independent tenure-track faculty position at a competitive research institution, so that I may continue to expand the exciting translational cancer immunotherapy project I have developed during my postdoctoral research career. This project aims to address a major problem in the dynamic field of cancer immunotherapy, namely, how to help cancer patients who lack intratumoral T cells respond more robustly to immunotherapy. I have devised a genetic screen approach to identify T cell genes that impact intratumoral T cell accumulation using Sleeping Beauty (SB) mutagenesis in two immunocompetent murine models of cancer (melanoma and lymphoma). We have identified a number of novel candidate immunotherapy targets that may enhance T cell mediated immunotherapies, including CAR-T cell adoptive transfer and immune checkpoint blockade (anti-PD-1). Aim 1 of this proposal directly tests the impact of promising candidate, Aak1, on T cell infiltration into tumors and its effect on anti-PD-1 efficacy, and Aim 2 expands on a successful pilot screen in order to identify additional candidates targets that are likely to synergize with anti-PD-1 therapy. Together these studies will promote the rational design of novel immunotherapeutic agents to enhance existing cancer therapy. I have extensive experience using SB mutagenesis, and my current training environment has allowed me to expand my research interests into the cancer immunotherapy field. The K22 award will be highly beneficial to my transition into an independent investigator, in part by allowing me to gain technical expertise in bioinformatics analysis as I seek formal training through the Masters in Bioinformatics program at the University of Iowa. These critical skills will allow me to fluently address pressing questions within the cancer immunology field, where the complexity of the tumor microenvironment necessitates a systems biology approach. Finally, my plan to advance to an independent investigator and establish a competitive independent research program includes applying for R01 level funding for this project in 2018. The K22 award will facilitate this process greatly, as the proposed work would lay the scientific foundation for a mechanistic grant proposal. Combined with my unique background and novel approach, NCI's K22 will help me launch a highly impactful, interdisciplinary research career in translational cancer immunology.

项目总结/摘要 我，劳拉·罗杰斯博士，博士，目前是爱荷华州霍尔顿大学的博士后研究员 综合癌症中心。我打算追求一个独立的终身教职，在竞争激烈的 研究机构，使我可以继续扩大令人兴奋的翻译癌症免疫治疗项目我 是在我的博士后研究生涯中发展起来的。该项目旨在解决一个主要问题， 癌症免疫治疗的动态领域，即如何帮助缺乏肿瘤内T细胞的癌症患者 对免疫疗法的反应更强。我设计了一种基因筛选方法来识别T细胞基因 使用睡美人（SB）诱变在两个肿瘤中影响肿瘤内T细胞积累 癌症（黑色素瘤和淋巴瘤）的免疫活性鼠模型。我们发现了一些新的 可能增强T细胞介导的免疫疗法的候选免疫疗法靶标，包括CAR-T细胞 过继转移和免疫检查点阻断（抗PD-1）。本提案的目标1直接测试了 有希望的候选物Aak 1对T细胞浸润到肿瘤中及其对抗PD-1功效的影响，以及目的2 在成功的试点屏幕上展开，以确定可能 与抗PD-1治疗协同作用。这些研究将促进小说设计的理性化 免疫抑制剂，以增强现有的癌症治疗。我有丰富的使用SB的经验 诱变，我目前的培训环境使我能够将我的研究兴趣扩展到 癌症免疫治疗领域。K22奖将非常有利于我过渡到独立的 调查员，部分原因是让我获得生物信息学分析的技术专长，因为我寻求正式的 通过爱荷华州大学的生物信息学硕士课程进行培训。这些关键技能将使 我流利地解决癌症免疫学领域的紧迫问题，其中的复杂性， 肿瘤微环境需要系统生物学方法。最后，我的计划是推进到一个 独立调查员和建立竞争性的独立研究计划，包括申请R 01 在2018年为该项目提供资金。K22奖将大大促进这一进程，因为拟议的工作 将为机械拨款提案奠定科学基础。结合我独特的背景， 新的方法，NCI的K22将帮助我启动一个非常有影响力的，跨学科的研究生涯， 转化癌免疫学