Immuno-cell therapy for brain tumors

摘要 胶质母细胞瘤(GBM)占所有成人脑肿瘤的50%，是最恶性的形式，长达5年。 患者存活率为3.3%。标准治疗包括最大限度的手术切除，然后是 放疗和化疗(替莫唑胺)；然而，正如低存活率所表明的那样，这些治疗 在预防疾病进展方面并不有效。胶质母细胞瘤具有高度的异质性。 神经干细胞亚群的一小部分，因其对常规疗法的抵抗而臭名昭著 对肿瘤复发和病人死亡负责。针对肿瘤细胞和胶质瘤的治疗方法 干细胞(GSCs)在保留正常细胞的同时，对这些患者将非常有益。独一无二的 哺乳动物嗅觉上皮持续替代其嗅觉感受器神经元的能力 在整个生命过程中，嗅鞘细胞的生理性转化和随后的损伤被归因于嗅鞘细胞 (OECs)，一种神经胶质细胞类型，在轴突从嗅觉上皮生长到 嗅球。嗅鞘细胞从外周神经系统迁移到中枢神经系统(CNS)， 嗅觉系统的发育和维持以及损伤后轴突延伸的关键过程 在神经再生方面。嗅鞘细胞释放扩散性因子吸引神经前体细胞进入吻部迁移 分流和调节它们的增殖和分化，并分化神经干细胞，导致 轴突延伸。由于它们强大的髓鞘形成和引导轴突生长的能力，神经保护作用， 以及它们的免疫调节和吞噬特性，评估了嗅鞘细胞的治疗潜力。 抗不同神经病理疾病的临床应用和作为治疗性转基因胶质瘤细胞的载体 但它们在体内的趋向性和抗胶质瘤作用尚未被研究。最近，我们为 第一次小鼠嗅鞘细胞自体移植可以靶向并将治疗性转基因输送到脑内 肿瘤通过鼻腔给药，这是嗅鞘细胞到达中枢神经系统的自然途径。在这项提议中，我们将以此为基础 嗅鞘细胞在胶质母细胞瘤干细胞治疗中的应用研究 和/或分化的GSCs，使其对传统疗法敏感，逆转免疫 抑制和激活抗肿瘤免疫。

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.