CAR T Cells for Advanced Thyroid Cancer

CAR T 细胞治疗晚期甲状腺癌

基本信息

批准号：
10600867
负责人：
THOMAS J FAHEY
金额：
$ 66.17万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2021-04-23 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600867
关键词：
Adjuvant Therapy Adopted Adoptive Cell Transfers Applications Grants Automobile Driving Biological Biological Markers Blood CAR T cell therapy CD19 gene Cancer cell line Categories Cells Characteristics Clinical Clinical Research Clonal Expansion Clonality Cytolysis Disease Distant Metastasis Dose Engineering Evaluation FDA approved Future Gene Expression Gene Expression Profile Goals Human I131 isotope Incidence Industry Collaboration Infusion procedures Institutional Review Boards Intercellular adhesion molecule 1 Investigational New Drug Application Kinetics Label Letters Malignant Neoplasms Malignant neoplasm of thyroid Measures Molecular Profiling National Cancer Institute Normal Cell Operative Surgical Procedures Outcome PD-1 blockade PET/CT scan Papillary Patients Pattern Phase Phase I Clinical Trials Prognosis Proliferating Radioactive Iodine Radiolabeled Recommendation Refractory Relapse Resistance Safety Site Solid Solid Neoplasm T cell clonality T-Lymphocyte Technology Testing Therapeutic Thyroid Gland Tissues Toxic effect Tracer Treatment Protocols Undifferentiated X-Ray Computed Tomography Xenograft Model alternative treatment anaplastic thyroid cancer cancer type cell type cellular imaging chimeric antigen receptor chimeric antigen receptor T cells clinical care clinical predictors cost cytokine design efficacy evaluation engineered T cells exhaustion fitness genetic signature improved in vivo liquid biopsy manufacture metabolic profile mouse model next generation novel therapeutics overexpression participant enrollment patient derived xenograft model patient population peripheral blood phase 1 study phase 2 study preclinical study response safety assessment single cell analysis somatostatin receptor 2 spatiotemporal standard care targeted treatment time use tumor tumor DNA virtual

项目摘要

Project Summary The overall incidence of thyroid cancer in 2016 was estimated by the National Cancer Institute to be 64,300. Patients who present with poorly differentiated thyroid cancers frequently are refractory to standard treatment regimens and have a much worse prognosis. The median overall survival in this patient population is less than a year. Undifferentiated or anaplastic thyroid cancers are typically not amenable to surgery and are highly resistant to RAI and virtually all other therapies. We therefore developed a chimeric antigen receptor (CAR) T cell therapy targeting intercellular adhesion molecule-1 (ICAM-1) (labeled as AIC100) to treat this aggressive type of thyroid cancer. While a variety of cells in the body normally express low, basal levels of ICAM-1, many human cancers have upregulated levels of expression. In particular, both refractory poorly differentiated and anaplastic thyroid cancers have greatly increased expression of ICAM-1. The key aspect of our CAR T cell technology is its ability to selectively kill tumors with over-expressed ICAM-1 while sparing normal cells with basal levels of ICAM-1 expression. To assess in vivo distribution of CAR T cells in both targeted tumors as well as non-target tissues, we have introduced the somatostatin receptor 2 (SSTR2) to follow CAR T cells over time using the clinically approved radiolabeled tracer 68Galium-DOTATATE (Netspot). In the planned phase I study, the primary objective is to assess the safety and determine the recommended dose of AIC100 for phase II study in patients with relapsed/refractory poorly differentiated thyroid cancer and in patients with anaplastic thyroid cancer. The secondary aims are to evaluate the efficacy of AIC100 in patients using PET/CT and RECIST (Response Evaluation Criteria In Solid Tumors) criteria, evaluate the feasibility of CAR T cell imaging by DOTATATE, determine if overall tumor response correlates with T cell distribution in tumor sites as measured by DOTATATE and other exploratory biomarkers, and to examine pre-infusion CAR T characteristics as a predictor of clinical response. Our investigational new drug (IND) application to open phase I study of AIC100 against advanced thyroid cancers is now approved by FDA in October 2019, and patient enrollment will commence in early 2020. As the cost for CAR T manufacturing and non-standard of care clinical costs will be sponsored by our industry collaborator (AffyImmune Therapeutics, Inc.), the major goals of this grant application are to assess the kinetics of T cell distribution by PET/CT, and determine the emergence of high clonality T cells and associated cellular and gene expression signatures with respect to clinical response, toxicity, and survival; to correlate intrinsic CAR T fitness for survival and clonal expansion with clinical response; to optimize T cell manufacturing and next-generation CAR designs to improve the fitness of CAR T cells toward more effective CAR T therapies against solid cancers.

项目摘要国家癌症研究所估计甲状腺癌在2016年的总体发病率为64,300。经常出现分化甲状腺癌的患者对标准治疗是难治性的方案，预后较差。该患者人群的中位总体生存率小于一年。未差异或间变性甲状腺癌通常不适合手术，并且高度高抗RAI和几乎所有其他疗法。因此，我们开发了嵌合抗原受体（CAR）T 细胞疗法靶向细胞间粘附分子1（ICAM-1）（标记为AIC100），以治疗这种侵略性甲状腺癌的类型。而体内的各种细胞通常表达低，基底水平的ICAM-1，许多细胞人类癌症的表达水平上调。特别是，耐火性的分化差，型甲状腺癌的ICAM-1表达大大增加。我们的汽车T细胞的关键方面技术是其具有过表达的ICAM-1选择性杀死肿瘤的能力，同时使用 ICAM-1表达的基础水平。评估靶向肿瘤中CAR T细胞的体内分布作为非目标组织，我们引入了生长抑素受体2（SSTR2），以跟随CAR T细胞随着时间的推移使用临床认可的放射性标记的示踪剂68钙含量（NetSpot）。在计划的第一阶段研究中，主要目的是评估安全性并确定II期AIC100的建议剂量对甲状腺癌的复发/难治性较差的患者进行研究甲状腺癌。次要目的是评估使用PET/CT和 RECIST（实体瘤的响应评估标准）标准，评估CAR T细胞成像的可行性通过dotatate，确定总体肿瘤反应是否与肿瘤部位的T细胞分布相关通过双齿酸盐和其他探索性生物标志物测量，并检查灌注前的汽车T 特征作为临床反应的预测指标。我们的调查新药（IND）应用于开放阶段我研究针对高级甲状腺癌的AIC100现已在2019年10月得到FDA的批准，患者入学率将于2020年初开始。作为汽车制造和非标准临床的成本成本将由我们的行业合作者（Affyimmune Therapeutics，Inc。）赞助，这是其中的主要目标赠款的应用是通过PET/CT评估T细胞分布的动力学，并确定高克隆性T细胞以及相关的细胞和基因表达信号相对于临床反应，毒性和生存；将固有的汽车t适应性与临床相关回复;优化T细胞制造和下一代汽车设计以提高汽车T的适应性细胞对针对固体癌症进行更有效的汽车疗法。