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.

项目概要美国国家癌症研究所估计，2016 年甲状腺癌的总发病率为 64,300 例。低分化甲状腺癌患者通常难以接受标准治疗的治疗方案，并且预后更差。该患者群体的中位总生存期低于一年。未分化或未分化的甲状腺癌通常不适合手术并且高度对 RAI 和几乎所有其他疗法具有抵抗力。因此我们开发了嵌合抗原受体（CAR）T 靶向细胞间粘附分子-1 (ICAM-1)（标记为 AIC100）的细胞疗法可治疗这种侵袭性甲状腺癌的类型。虽然体内多种细胞通常表达低水平的 ICAM-1，但许多细胞人类癌症的表达水平上调。特别是，难治性低分化和甲状腺未分化癌 ICAM-1 的表达大大增加。我们的 CAR T 细胞的关键方面技术的关键在于它能够选择性地杀死过度表达的 ICAM-1 肿瘤，同时不伤害正常细胞 ICAM-1 表达的基础水平。评估 CAR T 细胞在两种靶向肿瘤中的体内分布作为非靶组织，我们引入了生长抑素受体 2 (SSTR2)，以随着时间的推移跟踪 CAR T 细胞使用临床批准的放射性标记示踪剂 68Galium-DOTATATE (Netspot)。在计划的第一阶段研究中，主要目标是评估安全性并确定 II 期 AIC100 的推荐剂量针对复发/难治性低分化甲状腺癌和间变性甲状腺癌患者的研究甲状腺癌。次要目标是评估 AIC100 对使用 PET/CT 的患者的疗效，以及 RECIST（实体瘤反应评估标准）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 DOTATATE 和其他探索性生物标志物进行测量，并检查输注前 CAR T 特征作为临床反应的预测因子。我们的研究性新药 (IND) 申请进入开放阶段 I AIC100 治疗晚期甲状腺癌的研究现已于 2019 年 10 月获得 FDA 批准，患者招募将于 2020 年初开始。由于 CAR T 制造和非标准护理临床的成本费用将由我们的行业合作者 (AffyImmune Therapeutics, Inc.) 赞助，该项目的主要目标拨款申请的目的是通过 PET/CT 评估 T 细胞分布的动力学，并确定是否出现高克隆性 T 细胞以及与临床反应相关的细胞和基因表达特征，毒性和生存；将 CAR T 生存和克隆扩增的内在适应性与临床相关联回复;优化 T 细胞制造和下一代 CAR 设计，提高 CAR T 的适用性细胞对实体癌进行更有效的 CAR T 疗法。