CAR T Cells for Advanced Thyroid Cancer

CAR T 细胞治疗晚期甲状腺癌

• 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
• 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

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 据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。 患有低分化甲状腺癌的患者通常对标准治疗无效 而且预后更差。该患者人群的中位总生存期小于 一年未分化或未分化甲状腺癌通常不适合手术，并且高度危险。 对RAI和几乎所有其他疗法都有抗性。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AIC 100）的细胞疗法治疗这种侵袭性 甲状腺癌的类型虽然体内多种细胞正常表达低水平的ICAM-1，但许多细胞表达ICAM-1的水平较低。 人类癌症具有上调的表达水平。特别是，难治性低分化和 间变性甲状腺癌的ICAM-1表达显著增加。我们的CAR T细胞的关键方面 这项技术的最大优势是它能够选择性地杀死ICAM-1过表达的肿瘤，同时保留正常细胞， 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（SSTR 2），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68镓-DOTATATE（Netspot）。在计划的I期研究中， 主要目的是评估安全性并确定II期研究中AIC 100的推荐剂量 在复发性/难治性低分化甲状腺癌患者和间变性甲状腺癌患者中进行的研究 甲状腺癌次要目的是评价AIC 100在使用PET/CT的患者中的疗效， RECIST（实体瘤疗效评价标准）标准，评价CAR T细胞成像的可行性 通过DOTATATE，确定总体肿瘤缓解是否与肿瘤部位的T细胞分布相关， 通过DOTATATE和其他探索性生物标志物测量，并检查输注前CAR T 作为临床反应的预测指标。我们的研究性新药（IND）申请进入开放阶段 AIC 100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 招生将于2020年初开始。由于CAR T制造和非标准临床护理的成本 费用将由我们的行业合作伙伴（AffyImmune Therapeutics，Inc.）赞助，主要目标是 资助申请是通过PET/CT评估T细胞分布的动力学，并确定 高克隆性T细胞和与临床应答相关的细胞和基因表达特征， 毒性和存活;将生存和克隆扩增的内在CAR T适应性与临床 响应;优化T细胞制造和下一代CAR设计，以提高CAR T的适应性 细胞，以更有效的CAR T疗法对抗实体癌。