Immuno-Cell Therapy for Brain Tumors

脑肿瘤的免疫细胞疗法

• 批准号: 10541215
• 负责人: XANDRA OWENS BREAKEFIELD
• 金额: $ 59.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541215
• 关键词: Adult; Affect; Antibodies; Autologous Transplantation; Axon; Biological; Brain; Brain Neoplasms; Cell Communication; Cell Proliferation; Cell Therapy; Cell secretion; Cells; Central Nervous System; Central Nervous System Neoplasms; Cessation of life; Chemotherapy and/or radiation; Clinic; Complement; Cues; Data; Development; Disease Progression; Excision; Glioblastoma; Glioma; Growth; Homing; Human; Immune; Immune response; Immunosuppression; Infiltration; Inflammatory; Injury; Intranasal Administration; Life; Maintenance; Malignant - descriptor; Mesenchymal; Mesenchymal Stem Cells; Modeling; Mus; Natural Immunity; Nerve Regeneration; Neurites; Neuroglia; Normal Cell; Olfactory Epithelium; Olfactory Pathways; Olfactory Receptor Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Peripheral Nervous System; Phagocytes; Physiological; Predisposition; Process; Proliferating; Property; Radiation; Recurrent tumor; Resistance; Role; Route; Shapes; Stream; Survival Rate; T-Lymphocyte; Therapeutic; Therapeutic Effect; Time; Tropism; Tumor Immunity; adaptive immune response; adaptive immunity; arm; cell killing; cell motility; cell type; chemokine; clinical translation; conventional therapy; cytokine; cytotoxic; efficacy evaluation; exhaust; immune activation; immunoregulation; in vivo; migration; neoplastic cell; nerve stem cell; neural; neurological pathology; neuroprotection; olfactory bulb; patient derived xenograft model; prevent; programmed cell death protein 1; sex; standard of care; stem cell differentiation; stem cell therapy; stem cells; stem-like cell; stemness; targeted treatment; temozolomide; therapeutic transgene; tumor; tumor growth

Abstract Glioblastoma (GBM) comprises >50% of all brain tumors in adults and is the most malignant form with a 5-year patient survival rate of 3.3%. Standard-of-care treatment involves maximal surgical resection followed by radiation and chemotherapy (temozolomide); however, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. Glioblastomas are highly heterogeneous with a small subpopulation of neural stem-like cells notorious for their resistance to conventional therapy and known to be responsible for tumor recurrence and patient death. Therapies that target tumor cells as well as glioma stem cells (GSCs), while sparing normal cells, would be highly beneficial for these patients. The unique capacity of mammalian olfactory epithelium in continuous replacing its olfactory receptor neurons by physiological turnover and following injury throughout life has been attributed to the olfactory ensheathing cells (OECs), a glial cell type that closely accompany the axons as they grow from the olfactory epithelium into the olfactory bulb. OECs migrate from the peripheral nervous system to the central nervous system (CNS), a critical process in the development and maintenance of the olfactory system and axonal extension after injury in neural regeneration. OECs release diffusible factors to attract neural progenitors into the rostral migratory stream and regulate their proliferation and differentiation and to differentiate neural stem cells leading to neurite extension. Owing to their strong ability to myelinate and guide axonal outgrowth, neuroprotective role, as well as their immunomodulatory and phagocytic properties, the therapeutic potential of OECs was evaluated against different neurological pathologies in the clinic and as a carrier for therapeutic transgene to glioma cells in culture, but their tropism and effect against gliomas in vivo were not studied. Recently, we showed for the first time that autologous transplantation of mouse OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal administration, the natural route of OECs to CNS. In this proposal, we will build on this study and evaluate the potential use of OECs for glioblastoma stem cell therapy by regulating proliferation and/or differentiation of GSCs, making them susceptible to conventional therapies, reversing immune supression and activating anti-tumor immunity.

抽象的 胶质母细胞瘤 (GBM) 占成人所有脑肿瘤的 50% 以上，是最恶性的形式，5 年生存期 患者生存率为3.3%。标准护理治疗包括最大程度的手术切除，然后 放疗和化疗（替莫唑胺）；然而，正如生存率低下所表明的那样，这些治疗 未能有效预防疾病进展。胶质母细胞瘤具有高度异质性 神经干细胞样细胞的小亚群，因其对传统疗法的抵抗而臭名昭著，并且已知 负责肿瘤复发和患者死亡。针对肿瘤细胞和神经胶质瘤的疗法 干细胞（GSC）在保留正常细胞的同时，对这些患者非常有益。独特的 哺乳动物嗅觉上皮持续替换其嗅觉受体神经元的能力 一生中的生理更新和后续损伤归因于嗅鞘细胞 （OEC），一种神经胶质细胞类型，当轴突从嗅觉上皮生长到嗅觉上皮时，会紧密伴随轴突。 嗅球。 OEC从周围神经系统迁移到中枢神经系统（CNS）， 损伤后嗅觉系统和轴突延伸的发育和维持的关键过程 在神经再生中。 OECs释放扩散因子以吸引神经祖细胞进入吻端迁移 流动并调节它们的增殖和分化，并分化神经干细胞，从而导致 神经突延伸。由于它们具有强大的髓鞘形成能力和引导轴突生长的能力，具有神经保护作用， 以及它们的免疫调节和吞噬特性，评估了 OEC 的治疗潜力 在临床上对抗不同的神经病理学，并作为神经胶质瘤细胞治疗性转基因的载体 在培养中，但尚未研究它们在体内的趋向性和对神经胶质瘤的作用。最近，我们为大家展示了 小鼠 OEC 的自体移植首次能够靶向并向大脑传递治疗性转基因 鼻内给药后的肿瘤，OEC 到达中枢神经系统的自然途径。在本提案中，我们将在此基础上 研究和评估 OEC 通过调节增殖进行胶质母细胞瘤干细胞治疗的潜在用途 和/或 GSC 的分化，使它们对传统疗法敏感，逆转免疫 抑制和激活抗肿瘤免疫。