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.

摘要 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。虽然放射化疗改善了 结果，受益主要是在携带MGMT基因低表达肿瘤的患者亚组中， 超过45%的患者。最初的研究表明，MGMT抑制剂O-6苄基鸟嘌呤（BG）消耗AGT并致敏 GBM呼叫TMZ然而，毒性很高，因此被放弃。 为了减少在放化疗中加入BG的造血毒性，将造血祖细胞（HPC）基因转染， 工程化以表达MGMT突变体（P140 K），该突变体首先由PI Gerson鉴定，其对BG具有低亲和力，但去除了O-6甲基， 加合物具有与AGT相似的功效。这种创新的方法保护造血祖细胞（HPC）免受BG/TMZ 在体外和体内临床前研究和早期临床试验中的治疗表明了临床疗效。 虽然我们最初的假设是，这种治疗策略将通过提高对剂量递增的耐受性来提高生存率， 化疗后，人们逐渐认识到免疫系统在控制癌症方面的重要性，这提出了额外的重要性 在初始试验设计中未预期的问题。所观察到的生存率的提高是否仅仅是由于 造血隔室导致对细胞毒性化疗的耐受性增加，如最初假设的那样？或者， 这种策略改变了抗肿瘤免疫免疫抑制亚群之间的平衡？哪些免疫亚群 被转导的P140 K-MGMT赋予化学抗性，这是否有助于治疗反应或抗性？ 为了解决这些问题，我们提出了一个合作项目之间的案例综合癌症中心（CCCC）和美国国立卫生研究院 临床中心（NIHCC）扩大正在进行的IND I期试验，并纳入来自 新诊断的GBM患者。改善的患者访问，临床专业知识，和独特的，尖端的免疫学 NCICC的监测能力将加快权责发生制，帮助评估这一复杂试验的可行性，并帮助量化 各种免疫亚群的数量和功能的变化，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调节剂的数量和功能的纵向变化。 细胞亚型的血液，骨髓和肿瘤微环境，同时记录治疗耐受化疗， 转导基因的持久性、整合位点的安全性和治疗后肿瘤突变谱的变化。我们的假设是 用MGMT-P140 K转导的HPC随后BG/TMZ治疗的GBM患者将：A）。更好地耐受治疗，维持 改善的造血和免疫功能，并显示增加的无进展存活和总存活;和B）。证明 治疗前后效应子和抑制子免疫亚群的比例改变。 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，因为这些研究具有互补性。 CCCC在基因工程HPC方面的专业知识;增加患者招募和独特的免疫监测 和临床专业知识。该项目还与PI之间正在进行的合作产生协同作用。