Vaccination with Irradiated Tumor Cells Pulsed with an Adjuvant That Stimulates NKT Cells Is an Effective Treatment for Glioma
Vaccination with Irradiated Tumor Cells Pulsed with an Adjuvant That Stimulates NKT Cells Is an Effective Treatment for Glioma
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DOI：
10.1158/1078-0432.ccr-12-0704
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发表时间：
2012-12-01
影响因子：
11.5
通讯作者：
Hermans, Ian F.
中科院分区：
文献类型：
--
作者：
Hunn, Martin K.;Farrand, Kathryn J.;Hermans, Ian F.
目的：尽管最近的治疗进展，多形性胶质母细胞瘤（GBM）患者的预后仍然非常差。有一个迫切需要开发新的疗法，为这种diseases.Experimental Design：我们使用了可植入的GL 261小鼠神经胶质瘤模型，以调查的治疗潜力的疫苗组成的静脉注射照射的全肿瘤细胞脉冲与免疫佐剂α-半乳糖神经酰胺（α-GalCer）。在更严格的治疗环境中，给予一剂疫苗联合耗竭调节性T细胞（Treg）导致43%的长期存活率和MRI检测到的肿块病变消失。从机制上讲，alpha-GalCer组分被证明是通过以CD 1d限制性方式刺激“不变的”天然免疫球蛋白样T细胞（iNKT细胞）来起作用的，这反过来又支持了CD 4（+）T细胞介导的适应性免疫应答的发展。将α-GalCer脉冲到肿瘤细胞上避免了由游离α-GalCer诱导的严重iNKT细胞无反应性。为了研究该疫苗的临床应用潜力，在GBM患者中评估了iNKT细胞的数量和功能，并显示其与年龄匹配的健康志愿者相似。此外，照射GBM肿瘤细胞脉冲与α-半乳糖苷酶能够刺激iNKT细胞和增强T-细胞的反应在vitro.Conclusions：注射照射肿瘤细胞加载α-半乳糖苷酶是一个简单的程序，可以提供有效的免疫治疗高级别胶质瘤患者。临床癌症研究; 18（23）; 6446-59。(C)2012年AACR。
Purpose: The prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor despite recent treatment advances. There is an urgent need to develop novel therapies for this disease.Experimental Design: We used the implantable GL261 murine glioma model to investigate the therapeutic potential of a vaccine consisting of intravenous injection of irradiated whole tumor cells pulsed with the immuno-adjuvant alpha-galactosylceramide (alpha-GalCer).Results: Vaccine treatment alone was highly effective in a prophylactic setting. In a more stringent therapeutic setting, administration of one dose of vaccine combined with depletion of regulatory T cells (Treg) resulted in 43% long-term survival and the disappearance of mass lesions detected by MRI. Mechanistically, the alpha-GalCer component was shown to act by stimulating "invariant" natural killer-like T cells (iNKT cells) in a CD1d-restricted manner, which in turn supported the development of a CD4(+) T-cell-mediated adaptive immune response. Pulsing alpha-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free alpha-GalCer. To investigate the potential for clinical application of this vaccine, the number and function of iNKT cells was assessed in patients with GBM and shown to be similar to age-matched healthy volunteers. Furthermore, irradiated GBM tumor cells pulsed with alpha-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro.Conclusions: Injection of irradiated tumor cells loaded with alpha-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma. Clin Cancer Res; 18(23); 6446-59. (C) 2012 AACR.