Kim Jennifer E, Patel Mira A, Mangraviti Antonella, Kim Eileen S, Theodros Debebe, Velarde Esteban, Liu Ann, Sankey Eric W, Tam Ada, Xu Haiying, Mathios Dimitrios, Jackson Christopher M, Harris-Bookman Sarah, Garzon-Muvdi Tomas, Sheu Mary, Martin Allison M, Tyler Betty M, Tran Phuoc T, Ye Xiaobu, Olivi Alessandro, Taube Janis M, Burger Peter C, Drake Charles G, Brem Henry, Pardoll Drew M, Lim Michael
Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland.
Department of Radiation Oncology, Johns Hopkins University, Baltimore, Maryland.
Clin Cancer Res. 2017 Jan 1;23(1):124-136. doi: 10.1158/1078-0432.CCR-15-1535. Epub 2016 Jun 29.
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. Clin Cancer Res; 23(1); 124-36. ©2016 AACR.
程序性死亡1（PD-1）和T细胞免疫球蛋白黏蛋白3（TIM-3）等检查点分子是负性免疫调节因子，在多形性胶质母细胞瘤中可能上调。在小鼠胶质瘤模型中，联合PD-1阻断和立体定向放射外科治疗（SRS）已显示可提高抗肿瘤免疫力并产生长期存活者。然而，肿瘤浸润淋巴细胞（TIL）可表达多种检查点，且≥2种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TIM-3的表达以及单独使用TIM-3阻断剂以及与抗PD-1和SRS联合使用时的抗肿瘤疗效。
将C57BL/6小鼠植入小鼠胶质瘤细胞系GL261-luc2，并随机分为8个治疗组：（i）对照组，（ii）SRS组，（iii）抗PD-1抗体组，（iv）抗TIM-3抗体组，（v）抗PD-1+SRS组，（vi）抗TIM-3+SRS组，（vii）抗PD-1+抗TIM-3组，以及（viii）抗PD-1+抗TIM-3+SRS组。评估生存期和免疫激活情况。
与单独使用抗TIM-3抗体相比，抗TIM-3抗体+SRS或抗TIM-3+抗PD-1的联合治疗可提高生存期。三联疗法导致总生存率达100%（P<0.05），与其他组相比有显著改善。长期存活者表现出免疫细胞浸润和活性增加以及免疫记忆。最后，在8例人类胶质母细胞瘤样本中的7例中检测到TIM-3阳性染色。
这是第一项关于联合PD-1和TIM-3阻断与放疗效果的临床前研究。我们还证明了TIM-3在人类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，该组合可能导致胶质瘤长期存活，并构成一种治疗多形性胶质母细胞瘤的新型免疫治疗策略。《临床癌症研究》；23(1)；124 - 36。©2016美国癌症研究协会。
