Novel nano-vaccine technology for inducing immunity against gliomas

摘要 尽管免疫检查点阻断在癌症治疗中取得了成功，但它们的使用只使 癌症患者。肿瘤用来抑制抗肿瘤免疫反应的多种机制有 阻碍了它们作为单一疗法的广泛使用，尤其是对胶质瘤。因此，存在着 迫切需要新的补充战略，以实现强大和持久的免疫反应 神经胶质瘤。尤其是突变的异柠檬酸脱氢酶-1(IDH1-R132H；mIDH1)是成人胶质瘤的标志。 我们已经开发出一种完全免疫的小鼠mIDH1模型，通过结合遗传损伤 利用睡美人在人类疾病中遇到的神经前体细胞基因组DNA 转座酶的研究表明，这些颅内肿瘤表现出人类mIDH1胶质瘤的特征。我们的长- 学期研究目标是开发能够通过有效的抗mIDH1实现免疫刺激的新策略 神经胶质瘤免疫力。我们在这项应用中的主要目标是设计一种强大而安全的平台疫苗 诱导针对mIDH1胶质瘤的强大、持久的抗肿瘤记忆T细胞反应的技术。对这件事 最后，我们开发了一种基于合成高密度脂蛋白(Shdl)的新疫苗技术。 纳米盘。我们已经证明，sHDL纳米盘有效地将抗原和佐剂分子输送到抗原- 提供细胞，并实现具有强大细胞毒性潜力的强大T细胞反应。在此，我们建议 评价sHDL纳米粒在基因工程小鼠胶质瘤模型中的治疗效果 可移植的颅内胶质瘤。具体地说，我们建议(1)优化我们的纳米技术，以改进 MIDH1抗原传递和诱导持久记忆T细胞对mIDH1胶质瘤的反应(Aim 1)；(2)评估其 MIDH1基因工程神经瘤神经球治疗mIDH1胶质瘤的疗效观察 模型(GEM)植入免疫活性小鼠(目标2)；(3)验证结合纳米盘的假说 通过标准护理(放射)和抗PD-L1免疫检查点封锁接种疫苗将产生强大的抗- MIDH1宝石中具有长期免疫记忆的mIDH1胶质瘤免疫。这些研究将带来新的 用于精确免疫治疗的纳米疫苗递送平台的灯光。更广泛地说，拟议的工作将 解决目前疫苗技术中的技术限制，并可能导致新的治疗方案 MIDH1胶质瘤患者。

Abstract Despite the success of immune checkpoint blockade in cancer therapy, their use has benefited only a subset of cancer patients. The multiple mechanisms utilized by tumors to inhibit an anti-tumor immune response have impeded their widespread use as monotherapies, and this is particularly true for gliomas. Therefore, there exists a critical need for new, complementary strategies for achieving powerful and durable immune responses against gliomas. In particular, mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. We have developed a fully immune competent murine mIDH1 model by incorporating genetic lesions encountered in the human disease into the genomic DNA of neural progenitor cells using Sleeping Beauty Transposase and shown that these intracranial tumors exhibit the hallmarks of human mIDH1 glioma. Our long- term research goal is to develop novel strategies that can achieve immune stimulation with potent anti-mIDH1 glioma immunity. Our main objectives in this application are to engineer a powerful and safe platform vaccine technology for inducing robust, durable anti-tumor memory T-cell responses against mIDH1 gliomas. To this end, we have developed a new vaccine technology based on synthetic high-density lipoprotein (sHDL) nanodiscs. We have shown that sHDL nanodiscs efficiently deliver antigens and adjuvant molecules to antigen- presenting cells and achieve strong T-cell responses with robust cytotoxic potential. Here, we propose to evaluate the therapeutic efficacy of sHDL nanoparticles in genetically engineered murine glioma models and transplantable intracranial gliomas. Specifically, we propose to (1) optimize our nanotechnology for improved mIDH1 Ag delivery and elicit durable memory T-cell responses against mIDH1 glioma (Aim 1); (2) evaluate their efficacy to eradicate mIDH1 gliomas using neurospheres derived from the mIDH1 genetically engineered glioma model (GEM) implanted into immunocompetent mice (Aim 2); (3) test the hypothesis that combining nanodisc vaccination with standard of care (radiation) and anti-PD-L1 immune checkpoint blockade will elicit robust anti- mIDH1 glioma immunity with long-term immunological memory in mIDH1 GEMs. These studies will shed new light on nano-vaccine delivery platforms for precision immunotherapy. More broadly, the work proposed will address current technical limitations in vaccine technologies and potentially lead to a new treatment option for mIDH1 glioma patients.