A novel cellular tumor vaccine strategy for mutant IDH1 glioma

摘要-项目3 儿童原发脑肿瘤从低级别(LGGs)到致死性高级别胶质瘤的进展 (HGGs)通常发生在10年内，传统疗法无法预防。虽然 由于时间充裕，免疫疗法似乎是治疗lgg肿瘤的理想替代治疗方法。 在切除和复发之间可以激发抗肿瘤免疫的窗口，试图 开发这种方法一直没有成功。在LGG中发现的最常见的突变IDHR132H是 位于异柠檬酸脱氢酶1(IDH1)基因，在所有肿瘤细胞中普遍表达。 不幸的是，尽管IDHR132H的流行和无处不在使其成为优秀的肿瘤疫苗靶点，但它 证明免疫原性很差，特别是在产生CTL反应方面。该项目旨在克服 这一障碍是通过为IDHR132H+胶质瘤的新的单核细胞疫苗接种策略建立原理证据而实现的。 该方法利用内源性抗原(Ag)交叉呈现途径，使用 常驻脾树突状细胞(DC)显著提高颅内IDH1R132H+小鼠的存活率 CT2A型肿瘤。我们的初步数据表明，该策略可能刺激抗IDH1R132H CD8+T细胞 回应。基于这些发现和其他初步数据显示Flt3L显著改善 单核细胞疫苗在黑色素瘤小鼠模型中的疗效，该项目将测试单核细胞 接种疫苗可诱导小鼠产生有效的抗IDH1R132H CTL反应，并可增强这些反应 通过Flt3L接种，单核细胞疫苗将安全地激发强大的抗IDH1R132H免疫 人类的反应。这个项目的目标是确定具体的机制， 单核细胞疫苗接种抑制IDH1R132H胶质瘤生长(AIM 1)，以确定Flt3L是否提高了 表达IDH1R132H的小鼠胶质瘤的单核细胞疫苗(AIM 2)，并确定IDH1R132H是否 单核细胞疫苗对人类是安全的和具有免疫原性的(目标3)。这些研究有望提供 证明一种全新的疫苗策略，单核细胞疫苗，可能与 Flt3L给药，在IDH1R132H胶质瘤动物模型中提供了优于替代方案的疗效， 确定实现这一效果的机制，并证明这一策略是安全和 相关患者群体中的免疫原性。如果成功，该项目将提供理论基础和关键 未来单核细胞疫苗接种研究所需的信息，这有可能显著改善 IDH1R132H表达的胶质瘤患者的预后。

ABSTRACT – Project 3 The progression of primary brain tumors in children from low grade (LGGs) to lethal high grade gliomas (HGGs) typically occurs over a 10 year period and is not prevented by traditional therapies. Although immunotherapy seems to be an ideal alternative therapeutic approach for LGG tumors due to the ample time window between resection and recurrence during which anti-tumor immunity can be stimulated, attempts to develop the approach have been unsuccessful. The most common mutation found in LGGs, IDHR132H, is located in the isocitrate dehydrogenase 1 (IDH1) gene and is ubiquitously expressed in all tumor cells. Unfortunately, although its prevalence and ubiquity make IDHR132H an excellent tumor vaccine target, it has proven to be very poorly immunogenic, especially in generating CTL responses. This Project aims to overcome this hurdle by establishing proof of principle for a novel monocyte vaccination strategy for IDHR132H+ gliomas. The approach exploits an endogenous antigen (Ag) cross-presentation presentation pathway that uses resident splenic dendritic cells (DC) to significantly improve the survival of mice bearing intracranial IDH1R132H+ CT2A tumors. Our preliminary data suggest that this strategy may stimulate anti-IDH1R132H CD8+ T cell responses. Building on these findings and additional preliminary data showing that Flt3L markedly improves monocyte vaccine efficacy in mouse models of melanoma, the Project will test the hypotheses that monocyte vaccination can induce effective anti-IDH1R132H CTL responses in mice, that these responses can be increased by Flt3L administration, and that monocyte vaccination will safely stimulate robust anti-IDH1R132H immune responses in humans. The objectives of this project are to determine the specific mechanisms by which monocyte vaccination inhibits IDH1R132H glioma growth (Aim 1), to determine if Flt3L improves the efficacy of monocyte vaccination for IDH1R132H-expressing gliomas in mice (Aim 2), and to determine if IDH1R132H monocyte vaccination is safe and immunogenic in humans (Aim 3). These studies are expected to provide proof of principle that an entirely novel vaccine strategy, monocyte vaccination, possibly in combination with Flt3L administration, provides superior efficacy to alternative strategies in animal models of IDH1R132H gliomas, determine the mechanisms by which this efficacy is achieved, and demonstrate that this strategy is safe and immunogenic in a relevant patient population. If successful, this Project will provide the rationale and critical information needed for future studies of monocyte vaccination, which has the potential to significantly improve outcomes in patients with IDH1R132H-expressing gliomas.