Studies examining quantitative in vivo imaging of breast cancer-targeted,therapeutic human mast cells

研究检查乳腺癌靶向治疗性人类肥大细胞的定量体内成像

基本信息

批准号：
10618003
负责人：
Chris L KEPLEY
金额：
$ 19.04万
依托单位：
LIBERTY UNIVERSITY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10618003
关键词：
Studies examining quantitative vivo imaging

项目摘要

ABSTRACT Breast cancer (BC) continues to be a serious health problem in the United States. The oncogene HER2/neu and the folate receptor alpha (FRa) are overexpressed in BC and validated targets for cancer therapeutics. The humanized IgG1 monoclonal antibody (Ab) trastuzumab (Herceptin®) has been approved by the FDA for the treatment of advanced BC and several humanized IgG Abs to FRa are in clinical trials. However, their efficacy is limited and additional strategies to target HER2/neu and FRa overexpressing tumors are still urgently needed. Interestingly, high densities of mast cells (MC) in BC tumors are associated with favorable prognoses. We discovered that human adipose cells can be differentiated into autologous, fully functional MC capable of releasing anti-tumor mediators TNF-a and GM-CSF upon FceRI stimulation and inducing BC cell death. In addition, we have shown for the first time that primary human MC and their stem cell precursors can be transduced with a lentiviral vector carrying green fluorescence (GFP) protein opening up the possibility they could be transduced with other tumor killing molecules (e.g. TRAIL, granzyme, etc.) to create new ways to treat BC by directing immune evading cells with anti-tumor agents to tumors. However, it is important to determine if the ADMC will target cancer cells in vivo, determine the initial pharmacokinetics of this interaction, and establish proof-of-principle in regards to efficacy. Our overall hypothesis is ADMC can be transduced with genetic imaging modules that will allow for the visualization and quantification of binding to luciferase transduced BC cells/tumors in vivo after i.v. injection. Herein, we will use a novel and safer lentivirus vector system to transduce ADMC with genetic modules that will allow for in vivo visualization without affecting BC cell killing capabilities by comparing their ability to induce BC cell death compared to non-transduced ADMC. Further, we will visualize and quantify ADMC binding to BC cells in vivo and assess overt signs of toxicology activity in xenograft tumor models.

抽象的乳腺癌（BC）在美国仍然是一个严重的健康问题。致癌基因 HER2/neu。叶酸受体 α (FRa) 在 BC 中过度表达，是癌症治疗的有效靶点。人源化 IgG1 单克隆抗体 (Ab) 曲妥珠单抗 (Herceptin®) 已获得 FDA 批准用于晚期 BC 的治疗和几种针对 FRa 的人源化 IgG 抗体正在进行临床试验。疗效有限，针对 HER2/neu 和 FRa 过表达肿瘤的其他策略仍在研究中 BC 肿瘤中肥大细胞 (MC) 的高密度与有利的相关。我们发现人类脂肪细胞可以分化为自体、功能齐全的 MC。能够在 FceRI 刺激后释放抗肿瘤介质 TNF-a 和 GM-CSF 并诱导 BC 细胞此外，我们首次证明原代人类 MC 及其干细胞前体可以导致死亡。用携带绿色荧光（GFP）蛋白的慢病毒载体转导，开启了它们的可能性可以与其他肿瘤杀伤分子（例如 TRAIL、颗粒酶等）转导，以创造新的治疗方法通过使用抗肿瘤药物引导免疫逃避细胞来进行BC然而，确定是否是很重要的。 ADMC 将靶向体内癌细胞，确定这种相互作用的初始药代动力学，以及建立关于功效的原理证明我们的总体假设是 ADMC 可以通过以下方式进行转导。基因成像模块可实现荧光素酶结合的可视化和定量静脉注射后体内转导 BC 细胞/肿瘤，我们将使用一种新型且更安全的慢病毒。载体系统用遗传可视化模块转导 ADMC，这将允许在体内而不影响通过比较诱导 BC 细胞死亡的能力与未转导的细胞相比，BC 细胞杀伤能力此外，我们将可视化和量化 ADMC 与体内 BC 细胞的结合，并评估 ADMC 的明显迹象。异种移植肿瘤模型中的毒理学活性。