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

基本信息

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
项目类别：
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

项目摘要

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髓母细胞瘤的纳米成型小分子免疫疗法 M. Sokolsky-Papkov，（PI）该项目着重于改善髓母细胞瘤的治疗。尽管具有侵略性和剧烈的多模式治疗，有30％被诊断为髓母细胞瘤的儿童仍会死于复发性疾病。冲浪者有随后的肿瘤的风险增加，通常留下严重和终身治疗相关的认知和运动缺陷。与当前疗法更有效，更安全的新型方式的发展至关重要改善髓母细胞瘤中的临床结果。癌症免疫疗法，患者自身免疫的利用治疗癌症的系统已成为癌症治疗中的一种强大的新策略。我们的合作者博士最近的一项研究 Dolores Hambardzyman，建议SHH髓母细胞瘤富含TAM，我们的数据表明这些 TAMS Express TLR7/8。 Imidazoquinoline Drug regiquimod [R848]，一种Toll样受体（TLR）7和8激动剂，是评估为单个药物或与疫苗结合进行调整是几项肿瘤学临床试验黑色素瘤，膀胱癌，神经胶质瘤和其他恶性肿瘤（ClinicalTrials.gov：NCT00470379，NCT00821652， NCT00960752，NCT01204684）。但是，Regiquimod几乎在中性生理pH上几乎不溶临床批准的公式可用于其系统或局部肿瘤内给药。我们已经加载了Regiquimod 进入我们的超高容量纳米颗粒聚合物胶束（PMS）平台。以前我们已经利用了这个平台提供SMO抑制剂Vismodegib，CDK4/6抑制剂palbociclib和Pik3/akt/mtor抑制剂Sapanisertib（Ink-128）。在POX PMS中递送可降低毒性并使这些药物有效，而免费药物在 SHH髓母细胞瘤的G-SMO小鼠基因工程小鼠模型（GEMM）。与基于细胞或衍生的患者不同这些小鼠的植入模型具有内源性肿瘤，形成完整的天然肿瘤环境和血脑屏障（BBB）。用痘病 - 股素原PMS（痘孢子PMS）的治疗显着增强了巨噬细胞的渗透肿瘤降低了肿瘤细胞的生存能力（PRB水平）和长时间的小鼠存活。该项目旨在获得机械数据以全身（IP）和本地（IT）给予痘痘RES PM的影响，并确定抗靶向SHH途径的肿瘤剂可以与POX-RES PMS协同作用，以改善治疗结果。具体目标为：1。划定痘痘PMS对肿瘤免疫状况，疾病进展和局部影响的描述 SHH髓母细胞瘤的GEMM模型中的治疗结果。 2。描述免疫细胞群体的贡献对痘痘PMS和3的治疗作用。确定靶向SHH途径的抗塑性剂是否可以与POX-RES PMS协同作用，以改善对SHH驱动的髓母细胞瘤的处理。