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

• 批准号: 10046899
• 负责人: Chris L KEPLEY
• 金额: $ 26.37万
• 依托单位: UNIVERSITY OF NORTH CAROLINA GREENSBORO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046899
• 关键词: Adipocytes; Adipose tissue; Affect; Affinity; Animal Model; Antibodies; Antigens; Antineoplastic Agents; Autologous; BT 474; Binding; Biological Assay; Biological Process; Breast Cancer Cell; Breast Cancer Model; Cell Death; Cells; Clinic; Clinical Trials; Complementary DNA; Connective Tissue; Cryopreservation; Drug Kinetics; ERBB2 gene; Effector Cell; Ensure; Epitopes; Equus caballus; Experimental Designs; FDA approved; FOLR1 gene; Firefly Luciferases; Fluorescence; Gene Delivery; Genetic; Granulocyte-Macrophage Colony-Stimulating Factor; Granzyme; Health; Home environment; Homing; Human; IgE; IgE Receptors; IgG1; Image; Immune; Immunoglobulin G; Immunotherapy; In Vitro; Infusion procedures; Injections; Kinetics; Laboratories; Lead; Lentivirus Vector; Luciferases; MDA MB 231; MS4A1 gene; Malignant Neoplasms; Mammary Neoplasms; Mast Cell Neoplasm; Mediator of activation protein; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Nude Mice; Oncogenes; Patients; Phenotype; Production; Proliferating; Prostate; Proteins; Renilla Luciferases; Source; System; TNF gene; TNFSF10 gene; Testing; Therapeutic; Time; Tissues; Toxicology; Trastuzumab; United States; Visualization; Woman; advanced breast cancer; anti-cancer; anti-cancer therapeutic; antitumor agent; base; bioluminescence imaging; cancer cell; cancer immunotherapy; cancer therapy; cell killing; density; efficacy study; erbB-2 Receptor; experimental study; imaging genetics; immunosuppressed; in vivo; in vivo imaging; malignant breast neoplasm; mast cell; mortality; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; peripheral tolerance; safety study; stem cells; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor xenograft; vector

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.

摘要 乳腺癌（BC）在美国仍然是一个严重的健康问题。癌基因HER 2/neu 和叶酸受体α（FRa）在BC中过表达，并被证实是癌症治疗的靶点。 人源化IgG 1单克隆抗体（Ab）曲妥珠单抗（Herceptin®）已被FDA批准用于 晚期BC的治疗和几种抗FRa的人源化IgGAb正在临床试验中。但他们的 有效性有限，靶向HER 2/neu和FRa过表达肿瘤的其他策略仍然存在。 迫切需要。有趣的是，BC肿瘤中肥大细胞（MC）的高密度与肿瘤的有利生长相关。 两杯我们发现，人脂肪细胞可以分化为自体的，功能齐全的MC 能够在FceRI刺激时释放抗肿瘤介质TNF-α和GM-CSF并诱导BC细胞 死亡此外，我们首次证明原代人类MC及其干细胞前体可以 用携带绿色荧光（GFP）蛋白的慢病毒载体转导， 可以用其他肿瘤杀伤分子（例如TRAIL、颗粒酶等）转导。创造新的治疗方法 BC通过将免疫逃避细胞与抗肿瘤剂一起导向肿瘤。然而，重要的是要确定， ADMC将在体内靶向癌细胞，确定这种相互作用的初始药代动力学， 建立关于有效性的原则证明。我们的总体假设是ADMC可以被 遗传成像模块，其将允许与荧光素酶结合的可视化和定量 在静脉内注射后，在体内观察转导的BC细胞/肿瘤。在此，我们将使用一种新的和更安全的慢病毒， 载体系统，以使ADMC与遗传模块结合，其将允许体内可视化而不影响 BC细胞杀伤能力，通过比较它们诱导BC细胞死亡的能力与非转导的BC细胞杀伤能力。 ADMC。此外，我们将在体内观察和量化ADMC与BC细胞的结合，并评估ADMC与BC细胞的明显迹象。 异种移植肿瘤模型中的毒理学活性。