Investigating immunophenotype and metabolism of TCR KO donor and third-party CD19-targeted chimeric antigen receptor T cells

研究 TCR KO 供体和第三方 CD19 靶向嵌合抗原受体 T 细胞的免疫表型和代谢

基本信息

批准号：
10302044
负责人：
Melody Smith
金额：
$ 16.71万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10302044
关键词：
Advisory Committees Affect Allogenic Area Attenuated Autologous B-Cell Acute Lymphoblastic Leukemia Bioinformatics Bone Marrow CAR T cell therapy CD19 gene CRISPR/Cas technology Cell Count Cell Death Cell Therapy Cell physiology Cells Cellular Metabolic Process Chimerism Clinical Clinical Data Committee Members Data Development Disease Dose Educational workshop Engineering Engraftment FDA approved Foundations Future Generations Genome engineering Goals Graft Rejection Hematologic Neoplasms Hematopoietic Neoplasms Immune system Immunobiology Immunocompromised Host Immunology Immunophenotyping Immunotherapy Incidence Knock-out Knowledge Laboratory Study Lead Leukemic Cell Leukocytes Lymphoma Lymphoma cell Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Mentors Mentorship Metabolic Metabolic Pathway Metabolism Mitochondria Morbidity - disease rate Mus Non-Hodgkin&apos s Lymphoma Outcome Oxygen Consumption Patients Physicians Positioning Attribute Pre-Clinical Model Records Recurrent disease Refractory Disease Relapse Research Research Project Grants Research Training Scientist Source T memory cell T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Index Time Training Work allograft rejection antitumor agent antitumor effect attenuation base career chimeric antigen receptor chimeric antigen receptor T cells clinical translation design effective therapy effector T cell engineered T cells exhaustion fatty acid oxidation genome editing graft failure graft versus host disease induction graft vs host disease hematopoietic cell transplantation high risk immune reconstitution improved in vivo innovation knowledge base leukemia/lymphoma metabolic profile mortality mouse model next generation novel pre-clinical preclinical study prevent programs relapse risk response skill acquisition tumor

项目摘要

Abstract Relapse is the most important cause of mortality after allogeneic hematopoietic cell transplant (allo-HCT), but little research progress has been made in several decades. Chimeric antigen receptors targeting CD19 (CD19 CARs) redirect T cell effector functions to eliminate CD19-expressing leukemia and lymphoma cells. However, many patients still relapse. The candidate has preclinical data indicating the feasibility of using genome editing to delete the endogenous T cell receptor (TCR) to reduce the alloreactivity of donor CD19 CAR T cells, but it is unknown how these TCR knockout (KO) cells will function in vivo as anti-tumor agents, to what extent graft- versus-host-disease (GVHD) will result, or how engineering impacts T cell metabolism. This knowledge is essential for progress toward creating readily available “off-the-shelf” CAR T cells for patients with hematologic malignancies. The overall objectives of the proposed research are to determine how donor and third-party TCR KO CD19 CAR T cells impact immune reconstitution, GVHD, and graft rejection in preclinical models, as well as to understand how removing the TCR impacts the immunometabolism of these cells. The central hypothesis is that potent anti-tumor effects as well as negligible GVHD and graft rejection can be demonstrated preclinically by using TCR KO CD19 CAR T cells (either donor or third-party) following allo-HCT, to produce superior outcomes to conventional CD19 CAR T cells following allo-HCT. This hypothesis will be tested in the proposed Specific Aims. This work will provide ideal training for the candidate as she prepares for her long-term career goal to lead an independent laboratory studying cellular therapeutics and allo-HCT. Memorial Sloan Kettering Cancer Center has a renowned immunology program, and Dr. Marcel van den Brink, the candidate’s primary mentor, is a leader in immunotherapy research. Her co-mentor and advisory committee members have diverse and complementary expertise, and all have strong track records of mentoring independent scientists. The candidate and her mentoring team have developed a rigorous training plan designed to increase her knowledge base in: 1) development of next-generation CAR T cells; 2) bioinformatics and programming; 3) cellular metabolism, metabolic flux, mitochondrial function, and metabolic analyses in CAR T cells; and 4) professional development skills. The candidate will undertake training in these areas through coursework, workshops, and mentorship. This research project and training will provide the foundation to establish her future career as an independent physician-scientist. The proposed studies are expected to generate findings that will guide future genome engineering of CAR T cells. The candidate’s aim is to launch an independent research program designing “off- the-shelf” CAR T cells, which are expected to provide much improved therapeutic options for a range of hematologic malignancies.

抽象的复发是同种异性造血细胞移植（Allo-HCT）后死亡率的最重要原因，但几十年来，几乎没有研究进展。靶向CD19的嵌合抗原受体（CD19） CARS）重定向T细胞效应子功能，以消除表达CD19的白血病和淋巴瘤细胞。然而，许多患者仍然中继。候选人具有临床前数据，表明使用基因组编辑的可行性删除内源性T细胞受体（TCR）以降低供体CD19 CAR T细胞的同种异体反应性，但它是未知这些TCR敲除（KO）细胞将如何在体内作为抗肿瘤剂的作用，在多大程度上移植与宿主 - 疾病（GVHD）相对于宿主 - 疾病，或工程如何影响T细胞代谢。这些知识是对于为血液学患者创建容易获得的“现成”汽车T细胞的进展至关重要恶性肿瘤。拟议研究的总体目标是确定捐助者和第三方TCR如何 KO CD19 CAR T细胞会影响临床前模型中的免疫核定，GVHD和谷物排斥，以及要了解去除TCR如何影响这些细胞的免疫代谢。中心假设是可以临时证明潜在的抗肿瘤作用以及可忽略的GVHD和谷物排斥通过使用Allo-HCT之后的TCR KO CD19 CAR T细胞（供体或第三方）在Allo-HCT之后，常规CD19 CAR T细胞的结果。该假设将在提出的具体目标。这项工作将为候选人提供理想的培训，为她的长期职业目标做准备，以领导独立的实验室研究细胞疗法和Allo-HCT。纪念斯隆·克特林癌中心有一个著名的免疫学计划，候选人的主要精神Marcel Van den Brink博士是领导者在免疫疗法研究中。她的同事和咨询委员会成员有潜水员和完善专业知识，所有人都有良好的心理独立科学家的记录。候选人和她指导团队制定了一项严格的培训计划，旨在增加她的知识基础：1）下一代汽车T细胞的发展； 2）生物信息学和编程； 3）细胞代谢，汽车T细胞中的代谢通量，线粒体功能和代谢分析； 4）专业发展技能。候选人将通过课程，讲习班和心态在这些领域进行培训。该研究项目和培训将为建立她作为独立的未来职业提供基础身体科学家。预计拟议的研究将产生指导未来基因组的发现汽车T细胞的工程。候选人的目的是启动一项独立研究计划，设计“ 架子的T型单元格，预计将为一系列的一系列提供大量改进的治疗选择血液学恶性肿瘤。