Reprogramming Exosomes for Novel Immunotherapy of Triple Negative Breast Cancer

重编程外泌体用于三阴性乳腺癌的新型免疫疗法

• 批准号: 10733734
• 负责人: Yong Zhang
• 金额: $ 51.18万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733734
• 关键词: Address; Affinity; Antibodies; Binding; Biological; Biology; Blood specimen; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Breast Cancer therapy; CD3 Antigens; Cell Line; Cellular Immunity; Cytotoxic T-Lymphocytes; Development; Dioxygenases; Effector Cell; Encapsulated; Epidermal Growth Factor Receptor; ErbB Receptor Family Protein; Evaluation; Extracellular Domain; Fostering; Generations; Goals; Human; Immune; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Lead; Ligands; Link; Mediating; Medical; Membrane Proteins; Monoclonal Antibodies; Mus; Nanotechnology; Organ; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Property; Protein Engineering; Pyrroles; Receptor Protein-Tyrosine Kinases; Regimen; Resistance development; Safety; Sampling; Specificity; Surface; T-Lymphocyte; Therapeutic; Toxic effect; Translations; Tumor Immunity; Tumor-Derived; Vesicle; anti-cancer; antibody immunotherapy; cancer immunotherapy; cell type; chemotherapy; clinical application; cytotoxic; cytotoxicity; design; drug development; effective therapy; engineered exosomes; exosome; humanized mouse; immune checkpoint; immunological synapse formation; immunoreactivity; improved; in vivo; indoleamine; inhibitor; innovation; insight; malignant breast neoplasm; novel; novel therapeutics; overexpression; pharmacologic; polypeptide; programmed cell death ligand 1; programmed cell death protein 1; receptor; targeted delivery; therapeutic candidate; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor necrosis factor ligand superfamily member 4

Abstract Triple negative breast cancer (TNBC) accounts for approximately 15-20% of breast cancers and is the most aggressive subtype of breast cancer. Given little efficacy for existing therapeutic regimens against a significant number of TNBC patients and continuously developed resistance of TNBC cells to chemotherapy, novel treatment strategies with significantly enhanced potency and safety are still urgently required to address unmet medical needs. Exosomes are natural membranous vesicles secreted by many types of cells and possess many important and invaluable features for drug development. By harnessing these unique biological and pharmacological properties of exosomes, we are aimed to develop innovative synthetic exosomes as a highly potent form of therapeutics with excellent safety profiles for treatment of TNBC. Aim 1 will be design, generation, and characterization of engineered exosomes that can potently activate TNBC-specific antitumor immunity. Aim 2 will be creation and evaluation of reprogrammed exosomes that can specifically induce immune responses toward TNBC tumors. Aim 3 will be elucidation of mechanism(s) of action for identified lead immunotherapeutic exosomes. Successful completion of this project will result in a new class of immunotherapeutics with excellent pharmacological properties, leading to rapid translation into clinical applications and a paradigm shift in TNBC therapy.

抽象的 三重阴性乳腺癌（TNBC）约占乳腺癌的15-20％，是最多的 乳腺癌的积极亚型。赋予现有的治疗方案的功效几乎没有疗效 TNBC患者的数量以及TNBC细胞对化学疗法的不断抗性，新型 仍然需要以明显提高的效力和安全性的治疗策略来解决未满足 医疗需求。外泌体是自然的膜囊泡，由许多类型的细胞分泌，并且拥有许多 药物开发的重要和宝贵的特征。通过利用这些独特的生物学和 外泌体的药理特性，我们的目的是发展创新的合成外泌体作为高度 具有出色安全性的有效治疗形式，可用于治疗TNBC。 AIM 1将是设计，一代， 以及可以有效激活TNBC特异性抗肿瘤免疫力的工程外泌体的表征。目的 2将是可以特异性诱导免疫反应的重编程外泌体的创建和评估 朝向TNBC肿瘤。目标3将是阐明鉴定铅免疫治疗的作用机制 外泌体。该项目的成功完成将导致新的免疫治疗药，非常出色 药理特性，导致快速转化为临床应用和TNBC的范式转移 治疗。