Nanoformulated small molecule immunotherapy for SHH medulloblastoma

SHH 髓母细胞瘤的纳米制剂小分子免疫疗法

• 批准号: 10544532
• 负责人: MARINA SOKOLSKY-PAPKOV
• 金额: $ 38.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544532
• 关键词: Adjuvant; Affect; Agonist; Antibodies; Antineoplastic Agents; Blood - brain barrier anatomy; CDK4 gene; CTLA4 gene; Cell Proliferation; Cell Survival; Cells; Child; Childhood Malignant Brain Tumor; Circulation; Clinical; Cognitive deficits; Combined Modality Therapy; Data; Development; Diagnosis; Disease Progression; Environment; Exposure to; Flow Cytometry; Formulation; Genetically Engineered Mouse; Glioma; Immune; Immune response; Immune system; Immunotherapy; Impairment; Implant; In Vitro; Infiltration; Left; Macrophage; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Micelles; Modality; Modeling; Mus; Neoplasms; Operative Surgical Procedures; Outcome; PIK3CG gene; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Physiological; Play; Polymers; Population; Proto-Oncogene Proteins c-akt; Radiation therapy; Recurrence; Recurrent disease; Recurrent tumor; Reporting; Retinoblastoma Protein; Risk; Role; SHH gene; Survivors; T cell infiltration; T-Lymphocyte; TLR7 gene; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Treatment outcome; Tumor Promotion; Tumor Tissue; Vaccines; aggressive therapy; alternative treatment; anti-tumor immune response; blood-brain tumor barrier; brain tissue; cancer clinical trial; cancer immunotherapy; cancer therapy; chemotherapy; cytokine; immune checkpoint; immunological status; improved; in vivo; inhibitor; innovation; interest; mTOR Inhibitor; medulloblastoma; melanoma; motor deficit; mouse model; nano; nanoparticle; neoplastic cell; novel; novel therapeutics; programmed cell death protein 1; resiquimod; response; small molecule; synergism; targeted agent; therapy outcome; timeline; transcriptome; treatment effect; treatment strategy; tumor; tumor growth; tumor microenvironment

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.

SHH髓母细胞瘤的纳米小分子免疫治疗 M.Sokolsky-Papkov，(PI) 本项目致力于提高髓母细胞瘤的治疗水平。尽管具有侵略性和剧毒的多模式 治疗后，30%被诊断为髓母细胞瘤的儿童仍将死于复发疾病。幸存者们已经 增加继发肿瘤的风险，往往需要接受与认知和运动相关的严重和终身治疗 赤字。开发比现有疗法更有效和更安全的新疗法在以下方面至关重要 改善髓母细胞瘤的临床预后。癌症免疫治疗，利用患者自身免疫 系统治疗癌症，已成为癌症治疗的一种强有力的新策略。我们的合作者Dr。 Dolores Hambardzymyan提出SHH髓母细胞瘤富含TAMs，我们的数据显示这些 TAMs表达TLR7/8。咪唑喹啉类药物Requimod[R848]是一种Toll样受体(TLR)7和8激动剂。 作为一种单一的药物或佐剂与疫苗联合使用进行评估的是几个肿瘤学临床试验 黑色素瘤、膀胱癌、胶质瘤和其他恶性肿瘤(ClinicalTrials.gov：NCT00470379，NCT00821652， NCT00960752、NCT01204684)。然而，利奎莫特在中性生理pH下几乎不溶于水，不存在 临床批准的配方，可用于全身或局部肿瘤内给药。我们已经装载了Requimod 进入我们的超大容量纳米粒子聚合胶束(PMS)平台。在此之前，我们曾利用此平台 提供SMO抑制剂vismodegib、CDK4/6抑制剂palbociclib和PIK3/AKT/mTOR抑制剂Sapanisertib(INK-128)。 在痘PM中给药降低了毒性并使这些药物有效，而免费药物在 G-Smo小鼠-SHH髓母细胞瘤的基因工程小鼠模型(GEMM)。与基于细胞或患者来源的细胞不同 这些小鼠有内源性肿瘤，形成完整的天然肿瘤环境和血脑屏障 (Bbb)。用POX-RESPS(POX-RES PMs)治疗可显著增强巨噬细胞对血管内皮细胞的渗透 肿瘤降低了肿瘤细胞的活性(pRb水平)，延长了小鼠的存活时间。该项目旨在获得机械性 评估系统管理(IP)和本地管理(IT)POX-RES PM的效果并确定抗POX-RES PM是否 靶向SHH途径的肿瘤药物可以与POX-RES PM协同作用，改善治疗结果。具体目标 1.描述POX-RES PM对肿瘤免疫状态、疾病进展和局部的影响 SHH髓母细胞瘤GEMM模型的治疗效果。2.描述免疫细胞群体的贡献 POX-RES PM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诱导的髓母细胞瘤的治疗。