Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model.
Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model.
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DOI：
10.1371/journal.pone.0101764
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lim M
中科院分区：
文献类型：
--
作者：
Belcaid Z;Phallen JA;Zeng J;See AP;Mathios D;Gottschalk C;Nicholas S;Kellett M;Ruzevick J;Jackson C;Albesiano E;Durham NM;Ye X;Tran PT;Tyler B;Wong JW;Brem H;Pardoll DM;Drake CG;Lim M
胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，预后不良。细胞毒性T淋巴细胞抗原 - 4（CTLA - 4）阻断抗体已显示出对多种实体瘤产生强大抗肿瘤免疫反应的能力。4 - 1BB（CD137）由活化的T淋巴细胞表达，并作为一种共刺激信号，促进细胞毒性功能。在此，我们在一种具有免疫能力的颅内GBM模型中评估一种联合免疫治疗方案，包括4 - 1BB激活、CTLA - 4阻断和局部放射治疗。
将GL261 - 荧光素酶细胞立体定向植入C57BL / 6小鼠的纹状体中。使用小动物放射研究平台，用由4 - 1BB激动剂抗体、CTLA - 4阻断抗体和局部放射治疗组成的三联疗法对小鼠进行治疗，并观察小鼠的存活情况。通过流式细胞术分析脑浸润淋巴细胞的数量。给予CD4或CD8耗竭抗体以确定辅助性T细胞和细胞毒性T细胞在该方案中的相对作用。为了评估这种免疫疗法产生抗原特异性记忆反应的能力，对长期存活的小鼠用GL261胶质瘤和B16黑色素瘤侧腹肿瘤再次进行攻击。
与接受局部放射治疗以及4 - 1BB激活和CTLA - 4阻断免疫治疗的小鼠相比，接受三联疗法治疗的小鼠存活率提高。接受三联疗法治疗的动物至少有50%长期无瘤存活。三联疗法治疗导致CD4⁺和CD8⁺肿瘤浸润淋巴细胞密度更高。从机制上讲，CD4⁺T细胞的耗竭消除了三联疗法的抗肿瘤功效，而CD8⁺T细胞的耗竭对治疗反应没有影响。
在局部放射治疗的情况下，4 - 1BB激活和CTLA - 4阻断的联合疗法通过一种依赖CD4⁺T细胞的机制提高了胶质瘤原位小鼠模型的存活率，并产生抗原特异性记忆。
Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
CTLA-4 阻断和 4-1BB 激活相结合，通过增加 T 细胞浸润、增殖和细胞因子产生来增强肿瘤排斥。
影响因子：
3.7
作者：
Curran MA;Kim M;Montalvo W;Al-Shamkhani A;Allison JP
通讯作者：
Allison JP
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1097/cji.0b013e3182562d59
发表时间：
2012-06
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Agarwalla P;Barnard Z;Fecci P;Dranoff G;Curry WT Jr
通讯作者：
Curry WT Jr