Disappearance of MMR-deficient subclones after controlled IL-12 and PD-1 inhibition in a glioma patient.
Disappearance of MMR-deficient subclones after controlled IL-12 and PD-1 inhibition in a glioma patient.
复制标题
DOI：
10.1093/noajnl/vdab045
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Horbinski C
中科院分区：
文献类型：
--
作者：
McCord M;Lukas RV;Amidei C;Demars N;Gelb A;Buck J;Sachdev S;Feldman A;Tate M;Dixit K;Brat DJ;Jennings L;Horbinski C
复发性高级别胶质瘤是侵袭性脑肿瘤，预后较差。它们仍然是一个未满足的医疗需求，部分原因是对免疫抑制肿瘤微环境的不完全了解。尽管针对程序性死亡 1 (PD-1) 的免疫检查点抑制剂可能具有治疗作用，但其功效可能因肿瘤浸润淋巴细胞的缺乏而受到限制。最近，受控 IL-12 基因治疗系统在增加神经胶质瘤免疫原性方面显示出了希望。该系统通过局部施用的腺病毒载体刺激局部 IL-12 的产生，该载体传递 IL-12 的遗传信息和转录开关。口服激活剂配体 veledimex (VDX) 可控制转录水平。 IL-12 活性导致下游 IFN-γ 的产生并增加肿瘤免疫原性。 1 最近的一项 1 期临床试验表明，受控 IL-12 治疗与神经胶质瘤肿瘤相关 T 细胞浸润中 PD-1 和 PD-L1 表达增加相关。 1 这支持了研究受控 IL-12 与免疫检查点抑制剂疗法相结合的概念。在这里，我们描述了一名患有复发性 4 级星形细胞瘤的患者的病例，其中替莫唑胺 (TMZ) 后 DNA 错配修复 (MMR) 缺陷的肿瘤亚克隆在给予受控 IL-12 和 PD-1 阻断后消失。这些数据表明免疫系统可以针对高级别神经胶质瘤。
Recurrent high-grade gliomas are aggressive brain tumors with a poor prognosis. They remain an unmet medical need, in part because of an incomplete understanding of the immunosuppressive tumor microenvironment. Although immune checkpoint inhibitors targeting programmed death 1 (PD-1) may have a therapeutic role, their efficacy may be limited by a paucity of tumor-infiltrating lymphocytes. Recently, the Controlled IL-12 gene therapy system has shown promise in increasing glioma immunogenicity. This system stimulates local IL-12 production through a locally administered adenoviral vector, which delivers genetic information for IL-12 and a transcription switch. An orally administered activator ligand, veledimex (VDX), controls transcription levels. IL-12 activity leads to downstream production of IFN-γ and increases tumor immunogenicity. 1 A recent phase 1 clinical trial showed that Controlled IL-12 therapy was associated with increased expression of PD-1 and PD-L1 in tumor-associated T-cell infiltrates in glioma. 1 This supports the concept of investigating Controlled IL-12 in combination with immune checkpoint inhibitor therapy. Here, we describe the case of a patient with a recurrent grade 4 astrocytoma in which post-temozolomide (TMZ) DNA mismatch repair (MMR)-deficient tumor subclones disappeared following administration of Controlled IL-12 with PD-1 blockade. These data demonstrate that the immune system can be engaged to target high-grade glioma.