An engineered oncolytic herpes virus expressing a full-length α-CD47 mAb for the treatment of GBM

一种表达全长 α-CD47 mAb 的工程溶瘤疱疹病毒，用于治疗 GBM

基本信息

批准号：
10696185
负责人：
Jianhua Yu
金额：
$ 15.52万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-13 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696185
关键词：
Adult Adult Glioblastoma Aftercare Animal Model Anti-CD47 Antibody Therapy Antibody titer measurement Binding Biological Markers Biological Products Biopsy Blood Brain CD47 gene CD47-SIRPα blockade Cancer Control Cancer Model Cells Chemistry Circulation Clinical Clinical Trials Code Collaborations Correlative Study Cytolysis Development Dose Eating Engineering Extracellular Fluid FDA approved Fc Receptor Foundations Future G207 Genes Glioblastoma Goals Growth Factor Half-Life Herpesviridae Herpesvirus 1 IgG1 IgG4 Immune Immune response Immunocompetent Immunocompromised Host Immunologic Deficiency Syndromes Immunotherapy In Vitro Infusion procedures Institution Integral Membrane Protein Intravenous Investigational Drugs Investigational New Drug Application Length Ligands Macrophage Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Mediating Microdialysis Modeling Monitor Monoclonal Antibodies Mus Natural Killer Cells Neurologic Oncolytic Oncolytic viruses Organ Outcome PTPNS1 gene Pathologic Patients Phagocytosis Phagocytosis Inhibition Phase Phase I Clinical Trials Process Protocols documentation Recommendation Recurrence Role SHPS-1 protein Safety Signal Pathway Signal Transduction Simplexvirus Site System Testing Therapeutic Monoclonal Antibodies Tissue Harvesting Tissues Toxic effect Tumor Burden Virus Virus Shedding Work analog anti-tumor immune response antibody immunotherapy antibody-dependent cell cytotoxicity antibody-dependent cellular phagocytosis biomarker identification cancer cell cancer type chemokine cohort cytokine data sharing efficacy study good laboratory practice improved improved outcome in vivo innovation insight intravenous administration manufacture mortality mouse model neoplastic cell novel oncolysis oncolytic herpes simplex virus oncolytic virotherapy peripheral blood phase 1 study pre-clinical preclinical safety preclinical study response response biomarker safety outcomes safety study scaffold small molecule inhibitor systemic toxicity timeline tumor tumor DNA tumor progression

项目摘要

PROJECT SUMMARY – PROJECT 1 The combination of oncolytic virotherapy (OV) and monoclonal antibody (mAb) immunotherapy has great potential for the treatment of glioblastoma (GBM), the most common malignant brain tumor without a cure. An OV carrying a mAb-coding gene can produce and release the mAb drug specifically at the tumor site as a safe, effective, and innovative delivery system. Prior to our study, this approach has not been previously explored using herpes simplex virus 1-based OV (oHSV). CD47 is a transmembrane protein widely expressed on cancer cells including GBM. It acts as a “don’t eat me” signal by functioning as a ligand to signal regulatory protein-α (SIRPα) expressed on macrophages, resulting in inhibition of phagocytosis. We have generated an oHSV that expresses a full-length anti-CD47 mAb on an IgG1 scaffold (OV-αCD47-G1) that is capable of inducing antibody- dependent cellular phagocytosis (ADCP) by macrophages and antibody-dependent cellular cytotoxicity (ADCC) by natural killer cells to eradicate GBM cells in vitro and in vivo, in addition to blockade of the CD47-SIRPα “don’t eat me” signaling pathway in macrophages. We have demonstrated that our novel OV-αCD47-G1 significantly improves the survival of GBM-bearing mice in orthotopic, immunocompetent, and immunodeficient models. Our central hypothesis is that OV-αCD47-G1 will be safe and effective at improving GBM treatment and its anti- tumor activity in the brain will be reflected by markers in the peripheral blood. Importantly, we have optimized and manufactured GMP-grade OV-αCD47-G1 to conduct the proposed studies and will initiate a phase I clinical trial for adults with GBM. In this proposal, we will evaluate both the systemic and regional immune responses in vivo following clinical-grade OV-αCD47-G1 administration and identify markers in the circulation that correlate with anti-tumor activity in the brain in GBM animal models (Aim 1); we will perform Investigational New Drug (IND)-enabling in vivo safety and efficacy studies using clinical-grade OV-αCD47-G1 (Aim 2); and we will determine the safety of administering a single intracerebral infusion of OV-αCD47-G1 in adult patients with recurrent GBM (Aim 3). To accomplish these objectives, we will utilize immunocompetent and immunocompromised GBM mouse models for our correlative and preclinical studies evaluating OV-αCD47-G1 prior to the phase I clinical trial. Upon conclusion, we will understand how to optimize OV-αCD47-G1 therapy to cure GBM. Further insight into this process, as will result from the implementation and completion of this proposal, is impactful as it will ultimately lead to a reduction in mortality for adults suffering from GBM.

项目摘要 – 项目 1 溶瘤病毒疗法（OV）和单克隆抗体（mAb）免疫疗法的结合具有巨大的优势具有治疗胶质母细胞瘤（GBM）的潜力，胶质母细胞瘤是最常见的恶性脑肿瘤，无法治愈。携带mAb编码基因的OV可以在肿瘤部位特异性产生和释放mAb药物，作为一种安全、在我们的研究之前，这种方法尚未被探索过。使用基于单纯疱疹病毒 1 的 OV (oHSV) 进行研究，CD47 是一种在癌症中广泛表达的跨膜蛋白。它通过充当信号调节蛋白-α 的配体来充当“别吃我”的信号。 (SIRPα) 在巨噬细胞上表达，导致吞噬作用受到抑制。在 IgG1 支架 (OV-αCD47-G1) 上表达全长抗 CD47 mAb，能够诱导抗体- 巨噬细胞依赖性细胞吞噬作用 (ADCP) 和抗体依赖性细胞毒性 (ADCC) 除了阻断 CD47-SIRPα 之外，通过自然杀伤细胞在体外和体内根除 GBM 细胞“不我们已经证明，我们的新型 OV-αCD47-G1 显着影响巨噬细胞中的“吃我”信号通路。提高原位、免疫功能正常和免疫缺陷模型中携带 GBM 的小鼠的存活率。中心假设是 OV-αCD47-G1 将安全有效地改善 GBM 治疗及其抗- 大脑中的肿瘤活动将通过外周血液中的标记物反映出来。重要的是，我们已经进行了优化。并生产了 GMP 级 OV-αCD47-G1 来进行拟议的研究，并将启动 I 期临床在这项提案中，我们将评估成人 GBM 的全身和区域免疫反应。临床级 OV-αCD47-G1 给药后体内检测并识别循环中相关的标记物在 GBM 动物模型中具有大脑抗肿瘤活性（目标 1）；我们将进行新药研究； (IND)-使用临床级 OV-αCD47-G1 进行体内安全性和有效性研究（目标 2）；确定对成年患者进行单次脑内输注 OV-αCD47-G1 的安全性为了实现这些目标，我们将利用具有免疫功能和功能的复发性 GBM。用于评估 OV-αCD47-G1 的相关和临床前研究的免疫功能低下 GBM 小鼠模型在 I 期临床试验结束之前，我们将了解如何优化 OV-αCD47-G1 疗法。进一步深入了解这一过程，这将是该项目实施和完成的结果。该提案具有影响力，因为它最终将降低患有 GBM 的成年人的死亡率。