NOT-gated CAR T cells to overcome on-target, off-tumor toxicity in AML

非门控 CAR T 细胞可克服 AML 中的靶向、肿瘤外毒性

基本信息

批准号：
10696150
负责人：
Rebecca Margaret Richards
金额：
$ 24.9万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696150
关键词：
Acute Myelocytic Leukemia Adaptor Signaling Protein Advisory Committees Antigen Targeting Antigens B lymphoid malignancy Bioinformatics Biological Models CAR T cell therapy CD19 gene Cell Line Cell-Mediated Cytolysis Cells Cellular biology Cytometry Data Data Set Development Development Plans Diagnosis Endothelial Cells Endothelium Engineering Environment Equilibrium Event Flow Cytometry Foundations Genetic Transcription Goals Green Fluorescent Proteins Growth Hematopoietic Hematopoietic stem cells Immune system Immunohistochemistry Immunology Immunotherapy Interruption Investigation Link Logic Malignant Neoplasms Measures Mediator Mentors Mentorship Non-Malignant Normal tissue morphology PTPN6 gene Patients Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physicians Predisposition Protein Dephosphorylation Protein Tyrosine Phosphatase Proteomics Receptor Activation Receptor Signaling Recurrence Regulation Reporter Research Activity Research Personnel Resources Safety Sampling Scientist Signal Transduction Signaling Molecule Stem cell transplant Structure Surface Survival Rate T-Cell Activation T-Cell Receptor Techniques Technology Testing Tissues Toxic effect Training Transcriptional Activation United States Universities Work acute myeloid leukemia cell acute toxicity antileukemic activity cancer cell candidate identification career development chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical translation cytotoxicity design education planning engineered T cells experimental study extracellular high dimensionality improved in vitro Model in vivo innovation interest leukemia leukemia initiating cell leukemic stem cell neoplastic cell next generation novel preservation protein expression receptor recruit skills success therapeutic target transcriptome sequencing transcriptomics transmission process tumor tumor specificity

项目摘要

PROJECT SUMMARY Each year, nearly 20,000 patients in the United States are diagnosed with acute myeloid leukemia (AML), and 5-year overall survival rates remain dismal despite high intensity chemotherapy and, in many cases, stem cell transplant. Success of chimeric antigen receptor (CAR) T cell therapy in patients with B cell malignancies has prompted intense interest in applying this revolutionary type of immunotherapy to AML. However, clinical translation has been limited by overlap of AML target expression on indispensable, healthy tissues, which increases their susceptibility to CAR T cell-mediated cytotoxicity. Endothelial cell toxicity is of particular concern for some AML targets under investigation. To advance CAR T cell therapy for AML, it is critically important to devise strategies to preserve anti-leukemic efficacy while simultaneously sparing normal tissue from on-target, off-tumor toxicity. The central hypothesis of this proposal is that antigen-specific inhibitory CARs (iCARs) can be engineered to modulate CAR T cell activation signals and will decrease on-target, off-tumor toxicity of AML CAR T cells. Guided by strong preliminary data, this hypothesis will be tested with three specific aims: 1) Identifying optimal inhibitory motifs to incorporate into iCAR-containing NOT-gated CAR T cells; 2) Defining mechanisms by which those inhibitory motifs within iCARs can interrupt CAR T cell signaling using advanced proteomic techniques; and 3) Determining endothelial-specific NOT-gate surface targets by integrating transcriptomic and proteomic data. Key innovations of this proposal include implementation of a targeted screen to identify a best- in-class iCAR that will be generalizable across targets and application of mass cytometry (CyTOF) to interrogate fundamental inhibitory signaling mediators in CAR T cells. While the immediate focus of this proposal is designing a NOT-gated CAR for AML, principles defined by these experiments will provide the framework for applying this technology broadly to other tumor types. The proposed research activities are part of a comprehensive career development plan that will build on past expertise of the applicant and are crucial to her development as an independent investigator focused on translational immunotherapy. In particular, the applicant will gain expertise in high dimensional proteomics and bioinformatics by taking advantage of the world class scientific and mentorship environment at Stanford University. The applicant will be mentored by Dr. Crystal Mackall, renowned for her work on fundamental CAR T cell immunology and translational immunotherapy, and co-mentored by Dr. Ravi Majeti, an expert on therapeutic targeting of AML stem cells. Under their guidance, along with the assembled advisory committee (including Drs. Kara Davis, Ansuman Satpathy, and Kenneth Weinberg) and specific educational plan, the applicant will receive the necessary support and resources to accomplish the proposed aims and efficiently transition to independence following the K08 training period.

项目概要美国每年有近 20,000 名患者被诊断患有急性髓系白血病 (AML)，尽管进行高强度化疗，并且在许多情况下使用干细胞治疗，但 5 年总体生存率仍然很低移植。嵌合抗原受体 (CAR) T 细胞疗法在 B 细胞恶性肿瘤患者中取得成功激起了人们对将这种革命性的免疫疗法应用于 AML 的浓厚兴趣。然而，临床翻译受到不可或缺的健康组织上 AML 靶标表达重叠的限制，这增加它们对 CAR T 细胞介导的细胞毒性的敏感性。内皮细胞毒性尤其值得关注对于一些正在调查的反洗钱目标。为了推进针对 AML 的 CAR T 细胞疗法，至关重要的是制定策略以保持抗白血病功效，同时保护正常组织免于靶向，肿瘤外毒性。该提案的中心假设是抗原特异性抑制性 CAR（iCAR）可以旨在调节 CAR T 细胞激活信号，并降低 AML CAR 的靶向、肿瘤外毒性 T 细胞。在强有力的初步数据的指导下，该假设将通过三个具体目标进行测试：1）确定整合到包含 iCAR 的非门控 CAR T 细胞中的最佳抑制基序； 2) 定义机制 iCAR 中的那些抑制基序可以使用先进的蛋白质组学来中断 CAR T 细胞信号传导技术； 3) 通过整合转录组学和蛋白质组数据。该提案的主要创新包括实施有针对性的筛选，以确定最佳的一流的 iCAR，可跨靶点推广并应用质谱流式细胞仪 (CyTOF) 进行询问 CAR T 细胞中的基本抑制信号传导介质。虽然该提案的直接重点是设计用于 AML 的非门控 CAR，这些实验定义的原则将为应用此提供框架技术广泛应用于其他肿瘤类型。拟议的研究活动是综合职业发展计划的一部分，该计划将建立在过去的基础上申请人的专业知识，对于她作为独立调查员的发展至关重要转化免疫疗法。特别是，申请人将获得高维蛋白质组学和利用斯坦福大学世界一流的科学和指导环境来学习生物信息学大学。申请人将受到 Crystal Mackall 博士的指导，她因在 CAR 基础研究方面的工作而闻名 T细胞免疫学和转化免疫疗法，由T细胞免疫学和转化免疫疗法专家Ravi Majeti博士共同指导 AML 干细胞的治疗靶向。在他们的指导下，以及组建的咨询委员会（包括 Kara Davis 博士、Ansuman Satpathy 博士和 Kenneth Weinberg 博士）和具体的教育计划，申请人将获得必要的支持和资源，以有效地实现拟议目标 K08 培训期结束后过渡到独立。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of clinical pathways to improve multidisciplinary care of high-risk pediatric oncology patients.

开发临床路径以改善高危儿科肿瘤患者的多学科护理。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Reschke, Agnes;Richards, Rebecca M;Smith, Stephanie M;Long, Adrienne H;Marks, Lianna J;Schultz, Liora;Kamens, Jennifer L;Aftandilian, Catherine;Davis, Kara L;Gruber, Tanja;Sakamoto, Kathleen M
通讯作者：
Sakamoto, Kathleen M