Chemoprotection & Immune Remodeling after Hematopoietic Progenitor Cell Gene Therapy for Glioblastoma

化学保护

• 批准号: 10470774
• 负责人: STANTON L. GERSON
• 金额: $ 21.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470774
• 关键词: Address; Affinity; Aftercare; Alkylating Agents; Alkylating Antineoplastic Agents; Blood; Bone Marrow; Cell Lineage; Cells; Chemoprotection; Chemoresistance; Clinical; Clinical Trials; Collaborations; Complex; Comprehensive Cancer Center; Coupled; Cytotoxic Chemotherapy; DNA Adducts; DNA alkyltransferase; Development; Diagnosis; Disease; Dose; Effector Cell; Equilibrium; Gene Transfer; Genes; Genetic Engineering; Geography; Glioblastoma; Goals; Hematopoietic; Hematopoietic stem cells; Immune; Immune system; Immunologic Monitoring; Immunosuppressive Agents; In Vitro; Laboratories; Lymphoid; Lymphopenia; MGMT gene; Malignant Neoplasms; Marrow; Mutation; Myelogenous; Myelosuppression; Newly Diagnosed; Normal Cell; Patients; Phase I Clinical Trials; Phase I/II Trial; Prognosis; Proteins; Radiation therapy; Recurrent tumor; Relapse; Research Personnel; Resistance; Safety; Site; Speed; Therapeutic; Toxic effect; United States National Institutes of Health; adduct; base; chemoradiation; chemotherapy; clinical center; clinical efficacy; cohort; cytokine; early phase clinical trial; gene therapy; immune function; improved; improved outcome; in vivo; inhibitor; innovation; integration site; interest; mutant; novel strategies; overexpression; patient subsets; phase I trial; phase II trial; preclinical study; pressure; repaired; resistance mechanism; temozolomide; therapy resistant; treatment effect; treatment response; treatment strategy; trial design; tumor; tumor microenvironment

ABSTRACT Glioblastoma (GBM) remains a devastating diagnosis with a median survival of 12-14 months. Although radio-chemotherapy improves outcomes, benefit is primarily in the subset of patients bearing tumors with low expression of the MGMT gene, which comprises less than 45% of all patients. Initial studies demonstrated that the MGMT inhibitor, O-6benzylguanine (BG) depletes AGT and sensitized GBM to TMZ. However, toxicity was high and this was abandoned. To reduce the hematopoietic toxicity of adding BG to chemoradiation, hematopoietic progenitor cells (HPCs) were genetically engineered to express an MGMT mutant (P140K) first identified by PI Gerson, which has low affinity to BG, but removes O-6 methyl adducts with similar efficacy as AGT. This innovative approach protects the hematopoietic progenitor cells (HPC) from BG/TMZ treatment in both in vitro and in vivo preclinical studies and early clinical trials suggest clinical efficacy. Although our original hypothesis was that this treatment strategy would improve survival by improving tolerance to dose-escalated chemotherapy, the emerging recognition of the importance of the immune system in controlling cancer has raised additional important questions not anticipated during initial trial design. Is the observed improved survival due simply to chemoprotecton of the hematopoietic compartment resulting in increased tolerance to cytotoxic chemotherapy as originally hypothesized? Alternatively, does this strategy alter the balance between anti-tumor immune immunosuppressive subpopulations? Which immune subpopulations might be rendered chemo-resistant by transduced P140K-MGMT, and does this contribute to treatment response or resistance? To address these questions, we propose a collaborative project between the Case Comprehensive Cancer Center (CCCC) and the NIH Clinical Center (NIHCC) to expand an ongoing active IND phase I trial and incorporate additional analysis of biospecimens from patients with newly diagnosed GBM. The improved patient access, clinical expertise, and unique, cutting edge immunological monitoring capabilities at the NCICC will speed up accrual, help assess the feasibility of this complex trial, and help quantify the changes in quantity and function of various immune subpopulations, which will markedly enhance the impact of this innovative treatment approach. The overall goal of this proposal is to define the longitudinal changes in both the quantity and function of immune cell subtypes in blood, marrow and the tumor microenvironment, while documenting treatment tolerance to chemotherapy, the persistence of the transduced gene, integration site safety, and changes in tumor mutation profile after treatment. Our hypothesis is that GBM patients treated with MGMT-P140K transduced HPC followed by BG/TMZ, will: A). tolerate treatment better, maintain improved hematopoietic and immune function, and demonstrate increased progression-free and overall survival; and B). demonstrate altered proportions of effector and suppressor immune subpopulations before and after treatment. The collaboration with NIHCC and intramural investigators is essential to these to these ongoing studies given the complementary expertise in genetically engineered HPCs at CCCC; the increased access for patient accrual and the unique immunological monitoring and clinical expertise at NIHCC. This project also synergizes with the ongoing collaboration between the PIs.

抽象的 胶质母细胞瘤 (GBM) 仍然是一种毁灭性的诊断，中位生存期为 12-14 个月。尽管放化疗改善了 结果，受益主要是患有 MGMT 基因低表达肿瘤的患者子集，其中包括较少 超过所有患者的 45%。初步研究表明，MGMT 抑制剂 O-6 苄基鸟嘌呤 (BG) 会消耗 AGT 并致敏 GBM 到 TMZ。但由于毒性较大，因此被放弃。 为了减少放化疗中添加 BG 的造血毒性，对造血祖细胞 (HPC) 进行了基因改造。 设计用于表达 PI Gerson 首次鉴定的 MGMT 突变体 (P140K)，该突变体与 BG 亲和力较低，但去除了 O-6 甲基 加合物与 AGT 具有相似的功效。这种创新方法可保护造血祖细胞 (HPC) 免受 BG/TMZ 的影响 体外和体内临床前研究和早期临床试验的治疗表明了临床疗效。 尽管我们最初的假设是这种治疗策略可以通过提高对剂量递增的耐受性来提高生存率 随着化疗的出现，人们逐渐认识到免疫系统在控制癌症方面的重要性，这引起了更多的重视。 初始试验设计期间没有预料到的问题。观察到的生存率提高是否仅仅是由于化学保护 正如最初假设的那样，造血室导致对细胞毒性化疗的耐受性增加？或者，是否 这种策略会改变抗肿瘤免疫和免疫抑制亚群之间的平衡吗？哪些免疫亚群可能 通过转导的 P140K-MGMT 使其产生化疗耐药性，这是否有助于治疗反应或耐药性？ 为了解决这些问题，我们提出了案例综合癌症中心 (CCCC) 和 NIH 之间的合作项目 临床中心 (NIHCC) 将扩大正在进行的 IND I 期试验，并纳入对生物样本的额外分析 新诊断的 GBM 患者。改进的患者获取途径、临床专业知识以及独特、前沿的免疫学 NCICC 的监测能力将加快应计速度，帮助评估这项复杂试验的可行性，并帮助量化 各种免疫亚群的数量和功能发生变化，这将显着增强这一创新的影响 治疗方法。该提案的总体目标是定义免疫数量和功能的纵向变化 血液、骨髓和肿瘤微环境中的细胞亚型，同时记录对化疗的治疗耐受性， 转导基因的持久性、整合位点的安全性以及治疗后肿瘤突变谱的变化。我们的假设是 使用 MGMT-P140K 转导 HPC 和 BG/TMZ 治疗的 GBM 患者将： A)。更好地耐受治疗，维持 改善造血和免疫功能，并提高无进展生存率和总生存率；和 B）。证明 治疗前后效应子和抑制子免疫亚群的比例发生了变化。 鉴于互补性，与 NIHCC 和校内研究人员的合作对于这些正在进行的研究至关重要 CCCC 在基因工程 HPC 方面的专业知识；增加患者累积的机会和独特的免疫学监测 以及 NIHCC 的临床专业知识。该项目还与 PI 之间正在进行的合作产生协同作用。