Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas.
Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas.
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DOI：
10.1158/1078-0432.ccr-15-1535
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发表时间：
2017-01-01
期刊：
影响因子：
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通讯作者：
Lim M
中科院分区：
文献类型：
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作者：
Kim JE;Patel MA;Mangraviti A;Kim ES;Theodros D;Velarde E;Liu A;Sankey EW;Tam A;Xu H;Mathios D;Jackson CM;Harris-Bookman S;Garzon-Muvdi T;Sheu M;Martin AM;Tyler BM;Tran PT;Ye X;Olivi A;Taube JM;Burger PC;Drake CG;Brem H;Pardoll DM;Lim M
检查点分子如程序性死亡-1（PD-1）和T细胞免疫球蛋白粘蛋白-3（TIM-3）是负性免疫调节因子，可能在多形性胶质母细胞瘤中上调。PD-1阻断和立体定向放射外科手术（SRS）联合治疗已被证明可提高抗肿瘤免疫力，并在鼠胶质瘤模型中产生长期存活者。然而，肿瘤浸润淋巴细胞（TIL）可表达多个检查点，≥2个检查点的表达对应于更耗竭的T细胞表型。我们研究了胶质瘤模型中的TIM-3表达以及单独的TIM-3阻断和与抗PD-1和SRS组合的TIM-3阻断的抗肿瘤功效。将鼠神经胶质瘤细胞系GL 261-luc 2植入C57 BL/6小鼠并随机分为8个治疗组：（i）对照，（ii）SRS，（iii）抗PD-1抗体，（iv）抗TIM-3抗体，（V）抗PD-1 + SRS，（vi）抗TIM-3 + SRS，（vii）抗PD-1 +抗TIM-3，和（viii）抗PD-1 +抗TIM-3 + SRS。评估存活率和免疫活化。与单独的抗TIM-3抗体相比，抗TIM-3抗体+ SRS或抗TIM-3 +抗PD-1的双重治疗改善了存活。三联疗法导致100%的总生存率（P < 0.05），与其他组相比有显著改善。长期存活者表现出增加的免疫细胞浸润和活性以及免疫记忆。最后，在8个人GBM样品中的7个中检测到TIM-3的阳性染色。这是第一次对PD-1和TIM-3双重阻断与辐射的作用进行临床前研究。我们还证明了TIM-3在人多形性胶质母细胞瘤中的存在，并为一种新的治疗组合提供了临床前证据，该治疗组合可能导致胶质瘤的长期生存，并构成了一种治疗多形性胶质母细胞瘤的新的免疫策略。
Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti- TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme.