Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas.
Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas.
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DOI：
10.1016/j.ijrobp.2012.12.025
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发表时间：
2013-06-01
影响因子：
7
通讯作者：
Lim, Michael
中科院分区：
文献类型：
--
作者：
Zeng, Jing;See, Alfred P.;Phallen, Jillian;Jackson, Christopher M.;Belcaid, Zineb;Ruzevick, Jacob;Durham, Nicholas;Meyer, Christian;Harris, Timothy J.;Albesiano, Emilia;Pradilla, Gustavo;Ford, Eric;Wong, John;Hammers, Hans-Joerg;Mathios, Dimitris;Tyler, Betty;Brem, Henry;Tran, Phuoc T.;Pardoll, Drew;Drake, Charles G.;Lim, Michael
多形性胶质母细胞瘤（GBM）是成人最常见的原发性脑肿瘤，放射治疗是主要的治疗方式之一。然而，尽管有最好的治疗方法，治愈率仍然很低。免疫疗法是一种很有前途的方式，可以与放射协同工作，放射已被证明可以增加抗原呈递并促进促炎性肿瘤微环境。程序性死亡-1（PD-1）是一种在活化和耗竭的T细胞上表达的表面受体，其在与其配体PD-L1结合后介导T细胞抑制，PD-L1在许多肿瘤类型（包括人GBM）上表达。我们在小鼠原位GBM模型中测试了抗PD-1免疫疗法与立体定向放射外科手术的组合。我们将荧光素酶转染的小鼠胶质瘤细胞系GL 261植入C57 BL/6小鼠颅内。将小鼠分成4个治疗组：（1）对照;（2）仅辐射;（3）仅抗PD-1抗体;和（4）辐射加抗PD-1抗体。量化总生存期。植入后第21天杀死小鼠，以评估脑/肿瘤、颈淋巴结和脾脏的免疫学参数。与单独使用任何一种方法相比，联合抗PD-1治疗加放射治疗证明了生存期的改善：对照组的中位生存期为25天，抗PD-1抗体组为27天，放射组为28天，放射加抗PD-1治疗组为53天（对数秩Mantle-Cox检验P<.05）。仅在联合给药组中观察到长期存活，在给药后第180+天有一部分（15%-40%）动物存活。植入后第21天的免疫学数据显示，与单一治疗组相比，联合治疗组中细胞毒性T细胞（CD 8 +/干扰素-γ+/肿瘤坏死因子-α+）的肿瘤浸润增加，调节性T细胞（CD 4 +/FOXP 3）减少。PD-1阻断和局部放射治疗的组合导致具有原位脑肿瘤的小鼠的长期存活。这些研究提供了强有力的临床前证据，支持在GBM患者中进行的联合试验。
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%–40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
影响因子：
6.4
作者：
Smith, Karin Enell;Fritzell, Sara;Siesjo, Peter
通讯作者：
Siesjo, Peter
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
11.5
作者：
Newcomb, Elizabeth W.;Demaria, Sandra;Formenti, Silvia C.
通讯作者：
Formenti, Silvia C.
影响因子：
4.4
作者：
Mostboeck, Sven;Lutsiak, M. E. Christine;Sabzevari, Helen
通讯作者：
Sabzevari, Helen