A novel cellular tumor vaccine strategy for mutant IDH1 glioma

摘要-项目3 儿童原发性脑肿瘤从低级别（LGGs）到致死性高级别胶质瘤的进展 HGG通常发生在10年内，并且不能通过传统疗法预防。虽然 免疫治疗似乎是LGG肿瘤的理想替代治疗方法， 切除和复发之间的窗口，在此期间可以刺激抗肿瘤免疫，试图 开发的方法都不成功。LGG中最常见的突变IDHR 132 H是 位于异柠檬酸脱氢酶1（IDH 1）基因中，在所有肿瘤细胞中普遍表达。 不幸的是，尽管IDHR 132 H的流行和普遍存在使其成为一个极好的肿瘤疫苗靶标，但它仍然是一个潜在的肿瘤疫苗靶点。 证明其免疫原性非常差，尤其是在产生CTL应答方面。该项目旨在克服 通过建立用于IDHR 132 H+神经胶质瘤的新型单核细胞疫苗接种策略的原理证明来克服这一障碍。 该方法利用内源性抗原（Ag）交叉呈递途径， 常驻脾树突状细胞（DC）显著改善颅内IDH 1 R132 H+小鼠的存活率 CT 2A肿瘤我们的初步数据表明，这种策略可以刺激抗IDH 1 R132 H的CD 8 + T细胞， 应答基于这些发现和额外的初步数据，显示Flt 3L显著改善了 单核细胞疫苗在黑色素瘤小鼠模型中的有效性，该项目将测试单核细胞 疫苗接种可以在小鼠中诱导有效的抗IDH 1 R132 H CTL应答，这些应答可以增加 通过Flt 3L施用，并且单核细胞疫苗接种将安全地刺激稳健的抗IDH 1 R132 H免疫 人类的反应。本项目的目标是确定具体机制， 单核细胞疫苗接种抑制IDH 1 R132 H胶质瘤生长（目的1），以确定Flt 3L是否改善免疫调节的功效。 单核细胞疫苗接种用于小鼠中IDH 1 R132 H表达性神经胶质瘤（目的2），并确定IDH 1 R132 H 单核细胞疫苗接种在人类中是安全的和免疫原性的（目的3）。预计这些研究将提供 原理证明，一种全新的疫苗策略，单核细胞疫苗接种，可能与 Flt 3 L给药在IDH 1 R132 H神经胶质瘤动物模型中提供了优于替代策略的上级功效， 确定实现这种疗效的机制，并证明这种策略是安全的， 在相关患者群体中具有免疫原性。如果成功，该项目将提供基本原理和关键 单核细胞疫苗接种的未来研究所需的信息，这有可能显着改善 IDH 1 R132 H表达胶质瘤患者的预后。

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.