Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma.
Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma.
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DOI：
10.1186/s40425-014-0043-z
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发表时间：
2015
影响因子：
10.9
通讯作者：
Johnson BD
中科院分区：
文献类型：
--
作者：
Jing W;Gershan JA;Weber J;Tlomak D;McOlash L;Sabatos-Peyton C;Johnson BD
多发性骨髓瘤的特征是骨髓中存在转化的肿瘤浆细胞，通常被认为是一种不治之症。成功的治疗可能需要多方面的方法，包括传统的药物治疗，免疫治疗和其他新的治疗方法。我们的实验室先前表明，短暂淋巴细胞耗竭（亚致死全身照射）和PD-1/PD-L1阻断的组合产生了能够消除已建立疾病的抗骨髓瘤T细胞反应性。我们假设，在低剂量、淋巴细胞耗竭性全身辐射的背景下，阻断检查点受体的组合将增强抗肿瘤免疫力。为了检验我们的中心假设，我们利用了5T33小鼠多发性骨髓瘤模型。用低剂量全身照射和PD-L1、LAG-3、TIM-3、CD48（2B4的配体）和CTLA 4的阻断抗体组合治疗骨髓瘤荷瘤小鼠。骨髓瘤小鼠骨髓的时间表型分析表明，PD-1，2B4，LAG-3和TIM-3蛋白在T细胞上表达的百分比升高。当PD-L1阻断与LAG-3、TIM-3或CTLA 4的阻断抗体组合时，观察到存活率的协同或累加增加（存活率从约30%提高到> 80%）。生存率的增加与肿瘤反应性CD8和CD4 T细胞频率的增加相关。当在体外用骨髓瘤细胞刺激时，来自治疗小鼠的CD8 T细胞产生升高水平的促炎细胞因子。细胞因子从分离自用PD-L1加CTLA 4阻断抗体处理的小鼠的CD4 T细胞自发释放。这些数据表明，阻断PD-1/PD-L1相互作用与其他免疫检查点蛋白结合，在淋巴细胞耗竭剂量的全身照射后提供协同抗肿瘤功效。该策略是骨髓瘤和其他血液恶性肿瘤的一种有前景的联合策略。本文的在线版本（doi：10.1186/s40425 - 014 - 0043-z）包含补充材料，可供授权用户使用。
Multiple myeloma is characterized by the presence of transformed neoplastic plasma cells in the bone marrow and is generally considered to be an incurable disease. Successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments. Our lab previously showed that a combination of transient lymphodepletion (sublethal whole body irradiation) and PD-1/PD-L1 blockade generated anti-myeloma T cell reactivity capable of eliminating established disease. We hypothesized that blocking a combination of checkpoint receptors in the context of low-dose, lymphodepleting whole body radiation would boost anti-tumor immunity. To test our central hypothesis, we utilized a 5T33 murine multiple myeloma model. Myeloma-bearing mice were treated with a low dose of whole body irradiation and combinations of blocking antibodies to PD-L1, LAG-3, TIM-3, CD48 (the ligand for 2B4) and CTLA4. Temporal phenotypic analysis of bone marrow from myeloma-bearing mice demonstrated that elevated percentages of PD-1, 2B4, LAG-3 and TIM-3 proteins were expressed on T cells. When PD-L1 blockade was combined with blocking antibodies to LAG-3, TIM-3 or CTLA4, synergistic or additive increases in survival were observed (survival rates improved from ~30% to >80%). The increased survival rates correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells. When stimulated in vitro with myeloma cells, CD8 T cells from treated mice produced elevated levels proinflammatory cytokines. Cytokines were spontaneously released from CD4 T cells isolated from mice treated with PD-L1 plus CTLA4 blocking antibodies. These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation. This strategy is a promising combination strategy for myeloma and other hematologic malignancies. The online version of this article (doi:10.1186/s40425-014-0043-z) contains supplementary material, which is available to authorized users.
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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：
7.2
作者：
Bos R;Marquardt KL;Cheung J;Sherman LA
通讯作者：
Sherman LA
影响因子：
11.2
作者：
Fourcade J;Sun Z;Pagliano O;Chauvin JM;Sander C;Janjic B;Tarhini AA;Tawbi HA;Kirkwood JM;Moschos S;Wang H;Guillaume P;Luescher IF;Krieg A;Anderson AC;Kuchroo VK;Zarour HM
通讯作者：
Zarour HM
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
10.1
作者：
Anderson, Ana C.
通讯作者：
Anderson, Ana C.