Combinatorial Immunotherapy using a Multivalent Drug Conjugate for GBM Treatment

使用多价药物偶联物进行 GBM 治疗的组合免疫疗法

基本信息

批准号：
10560392
负责人：
Waldemar Debinski
金额：
$ 59.47万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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：
2022-12-09 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10560392
关键词：
Address Affinity Antineoplastic Agents Antitumor Response Bacterial Toxins Binding Biopsy Blood Brain Canis familiaris Catheters Cell Separation Cells Clinical Combination immunotherapy Complement Convection Cytotoxic agent Cytotoxin Development Disease Management Dose Dose Limiting Doxorubicin Drug Monitoring EPHA3 gene EphA2 Receptor EphB2 Receptor Ephrins Excision Genotype Glioblastoma Glioma Heterogeneity IL13RA1 gene IgG1 Immune response Immune system Immunologics Infiltration Interleukin-13 Intravenous Ligand Binding Long-Term Survivors Macrophage Magnetic Resonance Imaging Medicine Microtubules Modality Molecular Molecular Target Mus Newly Diagnosed Patients Pharmaceutical Preparations Pharmacologic Substance Phase I Clinical Trials Phenotype Play Primary Brain Neoplasms Primary Neoplasm Property Pseudomonas aeruginosa toxA protein Quality of life Recurrence Recurrent tumor Reflux Research Resistance Rodent Role Stains Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect Tumor Volume Tumor-associated macrophages Tumorigenicity antitumor effect assault design drug distribution effective therapy experimental study human disease human model improved in situ vaccination interest malignant breast neoplasm monocyte mutant neoplastic cell neovasculature novel overexpression receptor response scaffold self-renewal stem cells stem-like cell success therapy resistant transcriptome sequencing translational model tumor tumor heterogeneity tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

SUMMARY Treatment of glioblastoma (GBM) represents an unmet need in medicine. We have been pursuing a therapeutic approach of delivering potent targeted and specific cytotoxins using continuously evolving convection-enhanced delivery. Patients with GBM over-express interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors that are present in various pathophysiological compartments of GBM and all four are expressed in tumor cells of the core of tumor, and in locally-infiltrating tumor cells, while EphA2 is also found in tumor neovasculature. Further, IL-13RA2, EphA2, and EphA3 are associated with, and play crucial roles in, the pathobiology of glioma stem-like cells. Finally, the EphA3 receptor are found in M2 GBM- associated macrophages. Thus, collectively, IL-13RA2, EphA2, EphA3 and EphB2 are over-expressed in principal GBM compartments shown to be involved in tumor progression and/or resistance to therapies. In a first-of-kind approach, we performed Phase I clinical trial in dogs with spontaneous gliomas, which represents a faithful model of human disease, using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. We observed exceptional anti-tumor responses, including several near complete regressions, prolongation of survival and excellent quality of life in this dose-finding trial, at no toxicity. In addition, we found evidence for immune system activation during the therapy. Encouraged by these results, we pursued the novel idea of targeting all four receptors instead of two with one pharmaceutical compound. One of the Eph receptor ligands, ephrinA5 (eA5), binds EphA2, EphA3 and EphB2 receptors. We have thus generated an agent based on eA5 and IL-13 mutants targeting all four receptors using an IgG1 scaffold (QUAD). In our initial experiments, the QUAD was conjugated to derivatives of Doxorubicin (Dox) or a derivative of Pseudomonas exotoxin A, PE38QQR, to generate single pharmaceutical agents and these drug conjugates retained their binding affinities towards the targeted receptors while demonstrating prominent killing activity on GBM cells. QUAD- Dox and QUAD-PE38QQR conjugates have already shown prominent, long-lasting anti-tumor effects in dogs with spontaneous glioma at no toxicity: 60, 88, and 91% of tumor volume regression in the treated dogs, respectively. Recently, we have conjugated QUAD to DM1, a microtubule-disrupting agent. The QUAD-DM1 is extremely potent on GBM cells with IC50s in low femtomolar range, ~50x better than the Dox/PE conjugates. Therefore, we will continue this exciting line of research through Specific Aims as follows. In Specific Aim 1, we will treat dogs with spontaneous newly diagnosed and recurrent high-grade gliomas with QUAD-DM1. In Specific Aim 2, we will examine immune responses and the phenotype and genotype of recurring tumors in the course of QUAD-DM1 therapy. Our approach addresses crucial issues of inter- and intra-tumoral heterogeneity and evokes an in situ vaccination or so called “tumor inflaming” effect. We envision that this all-out assault, termed by us “molecular resection”, will result in a more effective management of GBM.

概括胶质母细胞瘤（GBM）的治疗代表了医学上未满足的需求。利用不断发展的技术提供有效的靶向和特异性细胞毒素的治疗方法 GBM 过度表达白介素 13 受体 α 2 (IL-13RA2) 的患者， EphA2、EphA3 和 EphB2 受体存在于 GBM 的各个病理生理室中所有四种蛋白均在肿瘤核心的肿瘤细胞和局部浸润的肿瘤细胞中表达，而 EphA2 此外，IL-13RA2、EphA2 和 EphA3 也与肿瘤新血管系统相关并发挥作用。最后，在 M2 GBM- 中发现了 EphA3 受体。因此，总的来说，IL-13RA2、EphA2、EphA3 和 EphB2 在主要的 GBM 区室被证明参与肿瘤进展和/或对治疗的抵抗。首创方法，我们在患有自发性神经胶质瘤的狗身上进行了 I 期临床试验，这代表我们使用针对 IL-13RA2 和 EphA2 受体的细胞毒素混合物建立了人类疾病的忠实模型。观察到异常的抗肿瘤反应，包括几次接近完全消退、延长在这项剂量探索试验中，我们发现了无毒性的生存率和良好的生活质量。受这些结果的鼓舞，我们追求了新的想法：用一种药物化合物靶向所有四种受体而不是两种， ephrinA5 (eA5) 结合 EphA2、EphA3 和 EphB2 受体，因此我们产生了基于 eA5 的药物。和 IL-13 突变体使用 IgG1 支架 (QUAD) 靶向所有四种受体。 QUAD 与阿霉素 (Dox) 衍生物或假单胞菌外毒素 A 衍生物缀合， PE38QQR，生成单一药剂并且这些药物缀合物保留其结合对目标受体的亲和力，同时对 GBM 细胞表现出显着的杀伤活性。 Dox 和 QUAD-PE38QQR 缀合物已在狗身上显示出显着、持久的抗肿瘤作用无毒性自发性神经胶质瘤：治疗犬的肿瘤体积消退 60%、88% 和 91%，最近，我们将 QUAD 与 DM1（一种微管破坏剂）结合。对 GBM 细胞极其有效，IC50 在低飞摩尔范围内，比 Dox/PE 缀合物好约 50 倍。因此，我们将通过具体目标继续进行这一令人兴奋的研究，具体目标 1 如下。将使用 QUAD-DM1 治疗患有自发性新诊断和复发性高级神经胶质瘤的狗。具体目标 2，我们将检查免疫反应以及复发肿瘤的表型和基因型我们的方法解决了肿瘤间和肿瘤内异质性的关键问题。并引发原位疫苗接种或所谓的“肿瘤炎症”效应，我们预计这种全面攻击，我们称之为“分子切除”，将使 GBM 得到更有效的治疗。