Immuno-cell therapy for brain tumors

摘要 胶质母细胞瘤（GBM）占成人所有脑肿瘤的>50%，并且是最恶性的形式，具有5年复发率。 患者生存率为3.3%。标准治疗包括最大限度的手术切除， 放疗和化疗（替莫唑胺）;然而，由于生存率低，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异质性， 一小群神经干细胞样细胞因其对常规治疗的抵抗而臭名昭著， 导致肿瘤复发和病人死亡靶向肿瘤细胞和神经胶质瘤的治疗 干细胞（GSC），而保留正常细胞，将是非常有益的这些患者。独特的 哺乳动物嗅上皮细胞持续替代嗅觉感受神经元的能力 生理周转和随后的损伤在整个生命过程中已被归因于嗅鞘细胞 嗅鞘细胞（OECs）是一种神经胶质细胞类型，当它们从嗅上皮生长到嗅鞘中时， 嗅球OECs从外周神经系统迁移到中枢神经系统（CNS）， 损伤后嗅觉系统发育和维持以及轴突延伸的关键过程 在神经再生中。嗅鞘细胞释放扩散因子吸引神经前体细胞进入吻侧迁移 并调节其增殖和分化，以及分化神经干细胞， 神经突延伸由于它们具有很强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，评价了OECs的治疗潜力 针对临床上不同的神经病理学和作为治疗性转基因到神经胶质瘤细胞的载体 在培养物中，但它们向性和体内抗胶质瘤的作用尚未研究。最近，我们展示了 小鼠OECs的自体移植首次可以靶向并向大脑递送治疗性转基因 鼻内给药后，OECs通过天然途径进入CNS。在本提案中，我们将在此基础上 研究和评估OECs通过调节增殖用于胶质母细胞瘤干细胞治疗的潜在用途 和/或GSC的分化，使它们对常规疗法敏感，逆转免疫应答， 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.