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.

纳米小分子免疫治疗SHH成神经管细胞瘤