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，但它们的使用仅使一部分人受益。 癌症患者。肿瘤利用多种机制来抑制抗肿瘤免疫应答， 阻碍了它们作为单一疗法的广泛使用，这对于神经胶质瘤尤其如此。因此，存在 迫切需要新的补充战略，以实现强大和持久的免疫反应， 神经胶质瘤特别是，突变型异柠檬酸脱氢酶-1（IDH 1-R132 H; mIDH 1）是成人神经胶质瘤的标志。 我们已经开发了一个完全免疫能力的小鼠mIDH 1模型， 在人类疾病中遇到的神经祖细胞的基因组DNA使用睡美人 转座酶，并表明这些颅内肿瘤表现出人类mIDH 1胶质瘤的标志。我们长久以来- 长期的研究目标是开发新的策略，可以实现免疫刺激与有效的抗mIDH 1 神经胶质瘤免疫我们在这一应用中的主要目标是设计一种强大而安全的平台疫苗 用于诱导针对mIDH 1神经胶质瘤的稳健、持久的抗肿瘤记忆T细胞应答的技术。本 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递送至抗原- 这些细胞可以被用于呈递细胞，并实现具有强大细胞毒性潜力的强T细胞应答。在此，我们建议 评估sHDL纳米颗粒在基因工程鼠胶质瘤模型中的治疗功效， 可移植性颅内胶质瘤具体来说，我们建议（1）优化我们的纳米技术，以改善 mIDH 1 Ag递送并引发针对mIDH 1胶质瘤的持久记忆T细胞应答（Aim 1）;（2）评估它们的 使用源自mIDH 1基因工程胶质瘤的神经球根除mIDH 1胶质瘤的功效 模型（GEM）植入免疫活性小鼠（目的2）;（3）测试组合纳米盘的假设， 用标准护理（辐射）和抗PD-L1免疫检查点阻断的疫苗接种将引发强有力的抗PD-L1抗体。 在mIDH 1 GEM中具有长期免疫记忆的mIDH 1胶质瘤免疫。这些研究将提供新的 为精确免疫治疗提供纳米疫苗输送平台。更广泛地说，拟议的工作将 解决目前疫苗技术的技术局限性，并可能导致一种新的治疗选择， mIDH 1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.