Naturally Targeted Exosomal TLR7/8 Agonist for Immunotherapy of Medulloblastoma

用于髓母细胞瘤免疫治疗的天然靶向外泌体 TLR7/8 激动剂

• 批准号: 10790660
• 负责人: ALEXANDER V KABANOV
• 金额: $ 42.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10790660
• 关键词: Adjuvant; Affect; Agonist; Animals; Biological Availability; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Brain Neoplasms; Cancer Patient; Cell Survival; Chemotherapy and/or radiation; Child; Childhood Malignant Brain Tumor; Clinical; Clinical Treatment; Cognitive deficits; Combined Modality Therapy; Data; Dendritic Cells; Development; Diagnosis; Drug Carriers; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Effector Cell; Encapsulated; Encephalitis; FDA approved; Formulation; Foundations; Gene Expression Profile; Generations; Genetically Engineered Mouse; Glioma; Goals; Immune system; Immunologic Stimulation; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infiltration; Inflammatory; Left; Macrophage; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Micelles; Modality; Modeling; Mus; Mutation; Myeloid Cells; Operative Surgical Procedures; Outcome; Parents; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Physiological; Positron-Emission Tomography; Prodrugs; Property; Radiation therapy; Recurrent disease; Retinoblastoma Protein; SHH gene; Solubility; Structure; Survivors; System; TLR7 gene; Testing; Therapeutic; Toll-like receptors; Tumor-associated macrophages; Vaccines; blood-brain tumor barrier; cancer clinical trial; cancer immunotherapy; carboxylesterase; cerebral capillary; chemotherapy; clinically relevant; design; drug distribution; exosome; extracellular vesicles; immune activation; immune cell infiltrate; improved; interest; medulloblastoma; melanoma; monocyte; motor deficit; mouse model; nanomicelles; nanopolymer; neoplastic cell; novel; novel strategies; novel therapeutics; pediatric patients; programs; resiquimod; side effect; treatment effect; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

Naturally Targeted Exosomal TLR7/8 Agonist for Immunotherapy of Medulloblastoma Despite aggressive and highly toxic treatment, nearly half of the children diagnosed with medulloblastoma will die from recurrent disease. Survivors are often left with disabling treatment-associated brain injury. More effective and less toxic therapies are needed to improve clinical outcomes for children affected by medulloblastoma. Sonic Hedgehog (SHH) medulloblastoma is enriched in tumor associated macrophages (TAMs) which express Toll-like receptor (TLR) 7 and 8. Reprogramming these TAMs could result in the loss of immunosuppressive signatures and acquisition of tumoricidal and proinflammatory signatures. We have shown that TLR7/8 agonist, resiquimod, encapsulated in polymeric nano-micelles significantly prolonged survival in G- Smo mice - genetically engineered mouse model (GEMM) of SHH medulloblastoma with intact blood brain barrier (BBB) and tumor microenvironment (TME). The free drug was not active in G-Smo mice medulloblastoma model. While micelles increase solubility and bioavailability of this agent to the brain capillaries, they do not target the BBB. Moreover, micelles are dynamic structures and release most of their cargo peripherally before reaching the brain, which can decrease therapeutic potential and increase side effects of this format. Hence, we propose a different formulation using monocyte/macrophage derived exosomes as natural targeted carriers of resiquimod for medulloblastoma. We discovered that exosomes secreted from macrophages are transported to the inflamed brain and carry therapeutic molecules across the intact BBB. Our preliminary data suggest that macrophage- derived exosomes accumulate in the brain of the G-Smo mice. Inspired by these discoveries we seek to develop exosome delivered resiquimod as a novel approach to medulloblastoma. Toward this goal we developed the exosome incorporated form of resiquimod (exo-Res) that was shown to polarize myeloid cells toward pro- inflammatory M1-like phenotype. We will test the hypotheses that (a) exo-Res exosomes in a G-Smo mouse model of medulloblastoma will effectively deliver the resiquimod to the tumor, (b) the delivered resiquimod will repolarize TAMs in medulloblastoma, (c) this novel targeted exo-Res therapeutic modality will inhibit the tumor growth and improve the clinically relevant outcomes compared to untargeted first generation nano-micelles, POx- Res PMs. Our Specific Aims will be: 1) Determine if exosomes improve the tumor distribution of resiquimod administered to medulloblastoma-bearing mice. SA2) Determine if exo-Res enhances the anti-tumor efficacy of resiquimod in medulloblastoma-bearing mice. If successful, this will lead to novel therapy that has potential to improve medulloblastoma treatment by replacing the current radiation and chemotherapy with the one that is less toxic and more effective.

天然靶向的外泌体TLR7/8激动剂用于髓母细胞瘤的免疫疗法 尽管有侵略性和剧烈的治疗，近一半被诊断为髓母细胞瘤的儿童将 死于复发性疾病。幸存者通常会留下与治疗相关的脑损伤。更多的 需要有效且毒性较低的疗法以改善受儿童影响的临床结果 髓母细胞瘤。 Sonic刺猬（SHH）髓母细胞瘤在肿瘤相关的巨噬细胞中富集 （TAM）表达类似收费的受体（TLR）7和8。重新编程这些TAM可能会导致丢失 免疫抑制特征以及肿瘤和促炎的签名。我们已经显示了 在聚合物纳米丝中封装的TLR7/8激动剂（重新摩托足动物）在G-中显着延长了生存率 SMO小鼠 - SHH髓母细胞瘤的基因工程小鼠模型（GEMM），具有完整的血脑屏障 （BBB）和肿瘤微环境（TME）。游离药物在G-SMO小鼠髓母细胞瘤模型中不活跃。 尽管胶束会增加该药物对脑毛细血管的溶解度和生物利用度，但它们并不针对 BBB。此外，胶束是动态结构，并在到达之前释放大部分货物 大脑可以降低治疗潜力并增加这种格式的副作用。因此，我们建议 使用单核细胞/巨噬细胞衍生的外泌体作为自然靶向载体的不同公式 用于髓母细胞瘤。我们发现从巨噬细胞分泌的外泌体被运输到发炎 大脑并在完整的BBB上携带治疗分子。我们的初步数据表明巨噬细胞 - 衍生的外泌体积聚在G-SMO小鼠的大脑中。受这些发现的启发，我们寻求发展 外泌体提供了resiquimod作为髓母细胞瘤的一种新方法。为了实现这一目标，我们开发了 外泌体融合形式的resiquimod（Exo-Res），该形式被证明会使髓样细胞偏振朝向前 炎症性M1状表型。我们将测试（a）G-SMO鼠标中的EXO-RES外泌体的假设 髓母细胞瘤的模型将有效地将重二摩托用于肿瘤，（b）已递送的Resiquimod将 （c）这种新颖的靶向外部外观治疗方式将抑制肿瘤 与未靶向的第一代纳米麦克雷相比，增长并改善了临床相关的结果 Res PMS。我们的具体目的是：1）确定外泌体是否改善了resiquimod的肿瘤分布 施用到含髓母细胞瘤的小鼠。 SA2）确定EXO-RES是否增强了抗肿瘤功效 在含有髓母细胞瘤的小鼠中的重quimimod。如果成功的话，这将导致具有潜力的新型治疗 通过替换当前的放疗和化学疗法来改善髓母细胞瘤的治疗 毒性较小，更有效。