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.

用于髓母细胞瘤免疫治疗的天然靶向外泌体 TLR7/8 激动剂 尽管采取了积极且剧毒的治疗，但近一半被诊断患有髓母细胞瘤的儿童仍会 死于复发性疾病。幸存者常常会留下与治疗相关的脑损伤，致残。更多的 需要有效且毒性较小的疗法来改善受该病影响的儿童的临床结果 髓母细胞瘤。 Sonic Hedgehog (SHH) 髓母细胞瘤富含肿瘤相关巨噬细胞 (TAM) 表达 Toll 样受体 (TLR) 7 和 8。重新编程这些 TAM 可能会导致丢失 免疫抑制特征以及杀肿瘤和促炎特征的获得。我们已经展示了 封装在聚合物纳米胶束中的 TLR7/8 激动剂雷西莫德可显着延长 G-细胞的存活时间 Smo 小鼠 - 具有完整血脑屏障的 SHH 髓母细胞瘤基因工程小鼠模型 (GEMM) （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没有活性。 虽然胶束增加了该药物在脑毛细血管中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，在到达外周之前会释放大部分货物 大脑，这会降低治疗潜力并增加这种形式的副作用。因此，我们建议 使用单核细胞/巨噬细胞衍生的外泌体作为雷西莫德天然靶向载体的不同配方 对于髓母细胞瘤。我们发现巨噬细胞分泌的外泌体被转运到发炎的部位 大脑并携带治疗分子穿过完整的血脑屏障。我们的初步数据表明巨噬细胞- 衍生的外泌体在 G-Smo 小鼠的大脑中积累。受到这些发现的启发，我们寻求开发 外泌体递送瑞西莫德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 外泌体掺入形式的雷西莫特 (exo-Res) 被证明可以使骨髓细胞极化为亲- 炎症 M1 样表型。我们将测试以下假设：(a) G-Smo 小鼠中的 exo-Res 外泌体 髓母细胞瘤模型将有效地将瑞西莫德递送至肿瘤，(b)递送的瑞西莫德将 使髓母细胞瘤中的 TAM 重新极化，(c) 这种新型靶向 exo-Res 治疗方式将抑制肿瘤 与非靶向第一代纳米胶束相比，POx- 能够促进生长并改善临床相关结果 回复 PM。我们的具体目标是：1) 确定外泌体是否改善雷西莫德的肿瘤分布 给予患有髓母细胞瘤的小鼠。 SA2)确定exo-Res是否增强了抗肿瘤功效 患有髓母细胞瘤的小鼠中使用雷西莫德。如果成功，这将带来新的疗法，有潜力 通过用现有的放疗和化疗替代现有的放疗和化疗来改善髓母细胞瘤的治疗 毒性更小，效果更佳。