Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
Agios Pharmaceuticals Inc, Cambridge, Massachusetts, USA.
J Immunother Cancer. 2022 May;10(5). doi: 10.1136/jitc-2022-004644.
Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.
An IDH1 glioma model was created in syngeneic -transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1 mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1 peptide vaccination or anti-PD-1 immune checkpoint blockade.
The -syngeneic IDH1 cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1 glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1 gliomas. AG-881 monotherapy suppressed the progression of IDH1 gliomas in a CD4 and CD8 cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4 tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1 peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1 and DR1-IDH1 peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.
The development of effective IDH1-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our -syngeneic IDH1 glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.
由于复发和恶性转化为高级别神经胶质瘤的风险较高，世界卫生组织（WHO）分级 II 级、异柠檬酸脱氢酶（IDH）突变型低级别神经胶质瘤（LGG）的长期预后较差。鉴于 LGG 患者的免疫系统相对完整，以及肿瘤生长速度较慢，免疫治疗策略很有吸引力。然而，在 IDH 突变型神经胶质瘤中，致癌代谢物 D-2-羟戊二酸（D-2HG）的积累导致肿瘤微环境中炎症途径受到抑制，从而导致“冷”肿瘤表型。抑制 D-2HG 的产生为肿瘤抗原疫苗接种和免疫检查点阻断后产生强大的抗肿瘤反应提供了机会。
在同基因转基因小鼠中创建了 IDH1 神经胶质瘤模型，使我们能够评估 HLA-DR1 限制性 IDH1 突变衍生的新表位的疫苗接种效果。评估了一种口服可用的突变型 IDH1 和 IDH2 抑制剂 AG-881 作为单一疗法以及与 IDH1 肽疫苗接种或抗 PD-1 免疫检查点阻断联合使用的效果。
-同基因 IDH1 细胞系表达 IDH1 突变蛋白，并在体内形成 D-2HG 产生的原位神经胶质瘤。用 AG-881 治疗荷瘤小鼠可使 IDH1 神经胶质瘤细胞（10 倍）和肿瘤相关髓样细胞中的 D-2HG 水平降低，IDH1 神经胶质瘤中肿瘤相关髓样细胞的 D-2HG 水平较高。AG-881 单药治疗以 CD4 和 CD8 细胞依赖性方式抑制 IDH1 神经胶质瘤的进展，增强促炎 IFNγ 相关基因表达，并增加 CD4 肿瘤浸润 T 细胞的数量。用 HLA-DR1 限制性 IDH1 肽或肿瘤相关 HLA-A2 限制性肽进行预防性疫苗接种并不能延长荷瘤动物的存活时间；然而，联合使用 IDH 抑制剂与 HLA-A2-IDH1 和 DR1-IDH1 肽疫苗接种可显著延长存活时间。最后，与单独使用任何一种治疗方法相比，用 AG-881 和 PD-1 阻断抗体治疗荷瘤小鼠可提高存活率。
通过与 HLA Ⅰ类限制性细胞毒性 T 细胞表位和 AG-881 整合，有效的 IDH1 靶向疫苗的开发可能会得到增强。我们的同基因 IDH1 神经胶质瘤模型应使我们能够评估与 IDH 突变型神经胶质瘤患者新策略的开发相关的关键转化问题。
