Department of Pathology, NYU Langone Health, New York, New York.
Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York.
Clin Cancer Res. 2019 Feb 15;25(4):1261-1271. doi: 10.1158/1078-0432.CCR-18-2312. Epub 2018 Nov 5.
Isocitrate dehydrogenase ()-mutant glioma is a distinct glioma molecular subtype for which no effective molecularly directed therapy exists. Low-grade gliomas, which are 80%-90% -mutant, have high RNA levels of the cell surface Notch ligand DLL3. We sought to determine DLL3 expression by IHC in glioma molecular subtypes and the potential efficacy of an anti-DLL3 antibody-drug conjugate (ADC), rovalpituzumab tesirine (Rova-T), in -mutant glioma.
We evaluated expression by RNA using TCGA data and by IHC in a discovery set of 63 gliomas and 20 nontumor brain tissues and a validation set of 62 known wild-type and mutant gliomas using a monoclonal anti-DLL3 antibody. Genotype was determined using a DNA methylation array classifier or by sequencing. The effect of Rova-T on patient-derived endogenous -mutant glioma tumorspheres was determined by cell viability assay.
Compared to wild-type glioblastoma, -mutant gliomas have significantly higher RNA ( < 1 × 10) and protein by IHC ( = 0.0014 and < 4.3 × 10 in the discovery and validation set, respectively). DLL3 immunostaining was intense and homogeneous in -mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 nontumor brains. Patient-derived -mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner.
DLL3 is selectively and homogeneously expressed in -mutant gliomas and can be targeted with Rova-T in patient-derived -mutant glioma tumorspheres. Our findings are potentially immediately translatable and have implications for therapeutic strategies that exploit cell surface tumor-associated antigens.
异柠檬酸脱氢酶（IDH）-突变型神经胶质瘤是一种独特的神经胶质瘤分子亚型，目前尚无有效的分子靶向治疗方法。低级别神经胶质瘤 80%-90%为 IDH 突变型，其细胞表面 Notch 配体 DLL3 的 RNA 水平较高。我们试图通过免疫组化（IHC）在神经胶质瘤分子亚型中检测 DLL3 的表达，并评估抗 DLL3 抗体药物偶联物（ADC）罗瓦替昔单抗（Rova-T）在 IDH 突变型神经胶质瘤中的潜在疗效。
我们使用 TCGA 数据评估了 RNA 中 DLL3 的表达，并使用一种针对 DLL3 的单克隆抗体在一个包含 63 例神经胶质瘤和 20 例非肿瘤脑组织的发现集以及一个包含 62 例已知 IDH 野生型和突变型神经胶质瘤的验证集中进行了 IHC 检测。通过 DNA 甲基化阵列分类器或测序确定基因型。通过细胞活力测定评估 Rova-T 对患者来源的内源性 IDH 突变型神经胶质瘤肿瘤球的影响。
与 IDH 野生型胶质母细胞瘤相比，IDH 突变型神经胶质瘤的 RNA（<1×10）和 IHC 检测的蛋白（在发现集和验证集中分别为=0.0014和<4.3×10）显著更高。IDH 突变型神经胶质瘤中 DLL3 的免疫染色强烈且均匀，在所有复发性肿瘤中均保留，而在 20 例非肿瘤脑组织中仅检测到 1 例。患者来源的 IDH 突变型神经胶质瘤肿瘤球过度表达 DLL3，并以抗原依赖性方式对 Rova-T 表现出强烈的敏感性。
DLL3 在 IDH 突变型神经胶质瘤中选择性且均匀地表达，可以用 Rova-T 对患者来源的 IDH 突变型神经胶质瘤肿瘤球进行靶向治疗。我们的发现具有潜在的即刻转化意义，并对利用细胞表面肿瘤相关抗原的治疗策略具有重要意义。
