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）仍然是毁灭性诊断，中位存活率为12-14个月。尽管放射化学疗法有所改善 结果，益处主要是在具有低表达的MGMT基因表达肿瘤的患者的子集中，其中包括较少 所有患者中的45％。最初的研究表明，MGMT抑制剂O-6BenzylGuanine（BG）耗尽并致敏 GBM到TMZ。但是，毒性很高，这被放弃了。 为了降低将BG添加到化学放疗的造血毒性，造血祖细胞（HPC）是遗传的 设计用于表达由Pi Gerson首次识别的MGMT突变体（P140K），该突变体对BG的亲和力较低，但删除了O-6甲基 与AGT相似的加合物。这种创新的方法保护造血祖细胞（HPC）免受BG/TMZ 体外和体内临床前研究和早期临床试验的治疗都表明临床功效。 尽管我们最初的假设是，这种治疗策略将通过提高剂量提升的耐受性来提高生存率 化学疗法，对免疫系统控制癌症重要性的新兴认识提出了其他重要 初始试验设计期间没有预见的问题。仅仅是由于仅仅是由于仅由于化学保护剂的改善而改善的生存率 造血室导致对最初假设的细胞毒性化学疗法的耐受性增加？或者，这样做 该策略改变了抗肿瘤免疫抑制亚群之间的平衡？哪些免疫亚群可能 通过转导的P140K-MGMT使化学抗性，这是否有助于治疗反应或抗性？ 为了解决这些问题，我们提出了一个案例综合癌症中心（CCCC）与NIH之间的合作项目 临床中心（NIHCC）扩大了正在进行的主动IND I期试验，并纳入了对生物测量的其他分析 新诊断为GBM的患者。改善患者的访问，临床专业知识和独特的尖端免疫学 NCICC的监视功能将加快应计，有助于评估该复杂试验的可行性，并有助于量化 各种免疫亚群的数量和功能的变化，这将显着增强这种创新的影响 治疗方法。该提案的总体目标是定义免疫的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，同时记录了对化学疗法的治疗耐受性， 治疗后转导的基因，整合位点安全性以及肿瘤突变谱的变化的持久性。我们的假设是 用MGMT-P140K治疗的GBM患者转导HPC，然后是BG/TMZ，WIRL：A）。更好地忍受治疗，保持 改善了造血和免疫功能，表现出无进展和整体存活的增加；和b）。证明 治疗前后的效应子和抑制器免疫亚群的比例改变。 与NIHCC和壁内研究人员合作对于这些正在进行的研究至关重要 CCCC的基因工程HPC的专业知识；患者应计和独特的免疫学监测的机会增加 以及NIHCC的临床专业知识。该项目还与PI之间的持续合作协同合作。