Nanoformulated small molecule immunotherapy for SHH medulloblastoma

纳米小分子免疫治疗SHH髓母细胞瘤 M. Sokolsky-Papkov，（PI） 该项目的重点是提高髓母细胞瘤的治疗。尽管有侵略性和高毒性的多模态 尽管如此，30%的被诊断患有髓母细胞瘤的儿童仍然会死于复发性疾病。幸存者 随后发生肿瘤的风险增加，并且通常会留下严重和终身治疗相关的认知和运动功能障碍。 赤字开发比当前疗法更有效、更安全的新疗法至关重要， 改善髓母细胞瘤的临床结局。癌症免疫治疗，利用患者自身免疫 系统治疗癌症，已经成为癌症治疗中一种强大的新策略。我们的合作者最近的一项研究，博士。 Dolores Hambardzymyan提出SHH髓母细胞瘤富含TAM，我们的数据显示这些TAM在SHH髓母细胞瘤中表达。 TAM表达TLR 7/8。一种咪唑并喹啉类药物瑞喹莫特[R848]，一种Toll样受体（TLR）7和8激动剂， 作为单一药剂或佐剂与疫苗组合进行评估的是在患有癌症的患者中进行的几项肿瘤学临床试验。 黑素瘤、膀胱癌、神经胶质瘤和其它恶性肿瘤（ClinicalTrials.gov：NCT 00470379，NCT 00821652， NCT 00960752、NCT 01204684）。然而，瑞喹莫特在中性生理pH下几乎不溶，并且不存在可溶性。 临床批准的制剂可用于全身或局部瘤内给药。我们已经装载了瑞喹莫特 我们的超高容量纳米颗粒聚合物胶束（PMs）平台。此前，我们曾利用该平台 递送SMO抑制剂vismodegib、CDK 4/6抑制剂palbociclib和PIK 3/AKT/mTor抑制剂Sapanisertib（INK-128）。 在POx PM中的递送降低了毒性并使这些药物有效，而游离药物在POx PM中没有显示出存活益处。 SHH髓母细胞瘤的G-Smo小鼠-基因工程小鼠模型（GEMM）。与基于细胞或患者来源的 这些小鼠具有形成完整的天然肿瘤环境和血脑屏障的内源性肿瘤 （BBB）。用POx-瑞喹莫特PM（POx-Res PM）处理显著增强了巨噬细胞向巨噬细胞中的浸润。 肿瘤降低了肿瘤细胞活力（pRB水平）并延长了小鼠存活。该项目旨在获得机械 评估全身（IP）和局部（IT）给予POx-res PM的效果，并确定抗- 靶向SHH途径的肿瘤剂可以与POx-res PM协同作用以改善治疗结果。具体目标 是：1.描述POx-res PM对肿瘤免疫状态、疾病进展和 SHH髓母细胞瘤GEMM模型的治疗结果。2.描述免疫细胞群的贡献 POx-res PMs的治疗效果和3.确定靶向SHH通路的抗肿瘤药物是否可以 与POx-res PM协同改善SHH驱动髓母细胞瘤的治疗。

Nanoformulated small molecule immunotherapy for SHH medulloblastoma M. Sokolsky-Papkov, (PI) This project focuses on improving therapy of medulloblastomas. Despite aggressive and highly toxic multi-modality therapy, 30% of the children diagnosed with medulloblastoma will still die from recurrent disease. The survivors have increased risk for subsequent neoplasms and are often left with severe and lifelong treatment-associated cognitive and motor deficits. Development of novel modalities that are more effective and safer than the current therapies is paramount in improving the clinical outcomes in medulloblastomas. Cancer immunotherapy, the utilization of the patients’ own immune system to treat cancer, has emerged as a powerful new strategy in cancer treatment. A recent study by our collaborator, Dr. Dolores Hambardzymyan, suggested that SHH medulloblastomas are enriched in TAMs and our data shows that these TAMs express TLR7/8. An imidazoquinoline drug resiquimod [R848], a Toll-like receptor (TLR) 7 and 8 agonist, is evaluated as a single agent or adjuvant in combination with vaccines is several oncology clinical trials in patients with melanoma, bladder cancer, glioma, and other malignancies (ClinicalTrials.gov: NCT00470379, NCT00821652, NCT00960752, NCT01204684). However, resiquimod is nearly insoluble at neutral physiological pH, and there is no clinically approved formulation available for its systemic or local intratumoral administration. We have loaded resiquimod into our ultrahigh-capacity nanoparticle polymeric micelles (PMs) platform. Previously we have utilized this platform to deliver SMO inhibitor vismodegib, CDK4/6 inhibitor palbociclib and PIK3/AKT/mTor inhibitor Sapanisertib (INK-128). Delivery in POx PMs reduced toxicity and rendered these agents effective, while free drugs showed no survival benefit in G-Smo mice-genetically engineered mouse model (GEMM) of SHH medulloblastoma. Unlike cells based or patient derived implantable models these mice have endogenous tumors which form intact native tumor environment and blood brain barrier (BBB). Treatment with POx-resiquimod PMs (POx-Res PMs) significantly enhanced infiltration of macrophages into the tumors decreased tumor cells viability (pRB levels) and prolonged mice survival. This project aims to obtain mechanistic data to evaluate the effects of POx-res PMs administered systemically (IP) and locally (IT) and determine whether the anti- neoplastic agents that target SHH pathway can synergize with POx-res PMs to improve treatment outcomes. Specific aims are: 1. Delineate systemic vs. local effects of POx-res PMs on the tumor immunological status, disease progression, and therapeutic outcomes in GEMM model of SHH medulloblastoma. 2. Delineate the contributions of immune cell populations to the therapeutic effect of POx-res PMs and 3. Determine whether the anti-neoplastic agents that target SHH pathway can synergize with POx-res PMs to improve treatment of SHH driven medulloblastoma.