The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue
The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue
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DOI：
10.1016/j.jconrel.2011.06.021
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发表时间：
2011-09-25
影响因子：
10.8
通讯作者：
Emerich, Dwaine F.
中科院分区：
文献类型：
--
作者：
Ali, Omar A.;Doherty, Edward;Emerich, Dwaine F.
我们之前设计了一种大孔的基于聚合物的疫苗，其最初产生GM-CSF梯度以招募局部树突状细胞，随后将CpG寡核苷酸和肿瘤裂解物呈递给细胞浸润，以诱导免疫细胞活化和对外周肿瘤模型中肿瘤细胞的免疫。在这里，我们证明，该系统根除已建立的颅内胶质瘤植入脑组织，而植入切除腔避免疫苗的效力。用植入肿瘤床中的PLC疫苗治疗携带七日龄颅内神经胶质瘤肿瘤的大鼠，导致对侧前肢功能的保留（第17天），其在对照动物中被肿瘤形成损害，以及90%的长期存活（>100天）。在接受肿瘤切除加疫苗植入相邻实质的动物中观察到类似的益处，但将PLC疫苗直接植入切除腔中没有益处。这种疗效的分离可能与GM-CSF分布有关，因为在脑组织内植入PLC疫苗长时间产生显著的GM-CSF梯度，而植入切除腔后未检测到。这些研究表明PLC疫苗功效与GM-CSF梯度形成相关，这需要直接植入脑组织，并证明进一步探索这种方法用于胶质瘤治疗是合理的。(C)2011 Elsevier B. V.保留所有权利。
We previously engineered a macroporous, polymer-based vaccine that initially produces GM-CSF gradients to recruit local dendritic cells and subsequently presents CpG oligonucleotides, and tumor lysate to cell infiltrates to induce immune cell activation and immunity against tumor cells in peripheral tumor models. Here, we demonstrate that this system eradicates established intracranial glioma following implantation into brain tissue, whereas implantation in resection cavities obviates vaccine efficacy. Rats bearing seven-day old, intracranial glioma tumors were treated with PLC vaccines implanted into the tumor bed, resulting in retention of contralateral forelimb function (day 17) that is compromised by tumor formation in control animals, and 90% long-term survival (>100 days). Similar benefits were observed in animals receiving tumor resection plus vaccine implants into the adjacent parenchyma, but direct implantation of PLC vaccines into the resection cavity conferred no benefit. This dissociation of efficacy was likely related to GM-CSF distribution, as implantation of PLC vaccines within brain tissue produced significant GM-CSF gradients for prolonged periods, which was not detected after implantation in resection cavities. These studies demonstrate that PLC vaccine efficacy is correlated to GM-CSF gradient formation, which requires direct implantation into brain tissue, and justify further exploration of this approach for glioma treatment. (C) 2011 Elsevier B.V. All rights reserved.