OR2H1 is an effective target for CAR T cells in human epithelial tumors

OR2H1是人类上皮肿瘤中CAR T细胞的有效靶点

基本信息

批准号：
10563356
负责人：
Jose R Conejo-Garcia
金额：
$ 19.55万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563356
关键词：
Ablation Antibodies Beds CAR T cell therapy Cancer Patient Cancer cell line Cell Therapy Cell surface Cellular Stress Cholangiocarcinoma Chronic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Conduct Clinical Trials Effectiveness Eligibility Determination Epithelium Esophagus Extracellular Domain Formulation Functional disorder Genetic Engineering Goals Hematologic Neoplasms Histologic Histology Human IgG1 Immunotherapy Infusion procedures Intervention Intrahepatic Cholangiocarcinoma Kidney Length Life Malignant Neoplasms Malignant neoplasm of prostate Mediating Metabolic Methods Monoclonal Antibodies Non-Small-Cell Lung Carcinoma Normal tissue morphology Organ Paralysed Pathway interactions Patients Prostate Proteins Recombinants Resistance Risk Signal Transduction Solid Solid Neoplasm Specificity Stains System T-Lymphocyte Technology Testis The Cancer Genome Atlas Therapeutic Tissues Toxic effect Translating Tumor Antigens Work XBP1 gene cancer type chimeric antigen receptor T cells design effector T cell empowerment endoplasmic reticulum stress engineered T cells experimental study first-in-human genetically modified cells high reward high risk in vivo mRNA Expression malignant stomach neoplasm neoplastic cell novel olfactory receptor patient derived xenograft model pre-clinical prevent prospective success tumor tumor growth tumor heterogeneity

项目摘要

ABSTRACT Identifying accessible tumor antigens that are not expressed in vital organs would allow genetic engineering of CAR T cells to avoid dysfunction at tumor beds. We have identified an olfactory receptor (OR) expressed in a variety of human tumors, ranging from ~70% of intrahepatic cholangiocarcinomas and 39% of prostate cancers, to ~10% of NSCLCs, and generated CAR T cells that specifically target its extracellular domain. The long-term goal of these studies is to translate these CAR T cells. Here, we will advance the preclinical work needed to apply for IND approval for a first-in-human clinical trial conducted at Moffitt, using OR2H1 CAR T cells generated in our Cell Therapy Facility under GMP conditions. Our central hypothesis is that genetically engineered OR2H1 CAR T cells can effectively control the progression of established tumors of different histologies, without the unacceptable on-target, off-tumor effects of other targets expressed in vital tissues. In Specific Aim 1, we will demonstrate the effectiveness and specificity of targeting OR2H1+ PDX with CAR T cells in vivo. These studies will support a rationale for subsequent IND approval for OR2H1 CAR T cell administration in patients with tumors expressing OR2H1 at variable levels. In Specific Aim 2, we will define the superiority of XBP1-ablated OR2H1 CAR T cells. These studies will support a rationale for genetic engineering of OR2H1 CAR T cells, to empower them to resist metabolic restrictions and inhibitory signals at tumor beds. In Specific Aim 3, we will optimize a method to identify eligible patients for OR2H1 CAR T cell targeting. Our work could exert a profound effect in the field by supporting a first-in-human clinical trial using OR2H1- targeted CAR T cells against a variety of solid human tumors, which could have significant benefits in a broad range of cancer patients, with limited or negligible toxicity.

抽象的识别在重要器官中不表达的可接近的肿瘤抗原将允许遗传 CAR T 细胞工程以避免肿瘤床功能障碍。我们已经确定了嗅觉受体（OR）在多种人类肿瘤中表达，范围从约 70% 的肝内胆管癌和 39% 前列腺癌，约 10% 的非小细胞肺癌，并产生了特异性靶向其细胞外结构域的 CAR T 细胞。这些研究的长期目标是转化这些 CAR T 细胞。在这里，我们将推进临床前工作需要申请 IND 批准在莫菲特进行的首次人体临床试验，使用 OR2H1 CAR T 细胞在我们的细胞治疗设施中在 GMP 条件下产生。我们的中心假设是基因工程化OR2H1 CAR T细胞可以有效控制不同类型已形成肿瘤的进展组织学，没有在重要组织中表达的其他靶点的不可接受的在靶点、肿瘤外效应。在具体目标 1 中，我们将展示靶向 OR2H1+ PDX 的有效性和特异性体内 CAR T 细胞。这些研究将为 OR2H1 CAR T 细胞后续 IND 批准提供依据对表达不同水平 OR2H1 的肿瘤患者进行给药。在具体目标 2 中，我们将定义 XBP1 消除的 OR2H1 CAR T 细胞的优越性。这些研究将支持 OR2H1 CAR T 细胞基因工程的基本原理，使其能够抵抗代谢肿瘤床的限制和抑制信号。在具体目标 3 中，我们将优化一种方法来识别符合 OR2H1 CAR T 细胞靶向的患者。通过支持使用 OR2H1- 的首次人体临床试验，我们的工作可以在该领域产生深远的影响针对多种人类实体瘤的靶向 CAR T 细胞，可能在广泛的领域产生显着的益处一系列癌症患者，毒性有限或可忽略不计。