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

项目摘要-项目1 溶瘤病毒疗法（OV）和单克隆抗体（mAb）免疫疗法的组合具有很大的优势。 胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤，目前尚无治愈方法。一个 携带mAb编码基因的OV可以在肿瘤部位特异性产生并释放mAb药物， 有效和创新的交付系统。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）。CD 47是一种跨膜蛋白，广泛表达于肿瘤组织中 包括GBM在内的细胞。它通过作为信号调节蛋白-α的配体发挥作用，作为“不要吃我”的信号 (SIRPα）在巨噬细胞上表达，导致吞噬作用受到抑制。我们已经生成了一个oHSV， 在IgG 1支架上表达全长抗CD 47 mAb（OV-α CD 47-G1），其能够诱导抗体- 巨噬细胞的依赖性细胞吞噬作用（ADCP）和抗体依赖性细胞毒性（ADCC） 通过自然杀伤细胞在体外和体内根除GBM细胞，除了阻断CD 47-SIRPα外， 吞噬我”的信号通路。我们已经证明，我们的新OV-α CD 47-G1显着 提高了原位、免疫活性和免疫缺陷模型中携带GBM小鼠的存活率。我们 中心假设是OV-α CD 47-G1将安全有效地改善GBM治疗，其抗 脑中的肿瘤活性将通过外周血中的标记物来反映。重要的是，我们优化了 并生产GMP级OV-α CD 47-G1进行拟议的研究，并将启动I期临床试验。 对患有GBM的成年人进行试验。在这个建议中，我们将评估全身和区域免疫反应， 临床级OV-α CD 47-G1给药后的体内研究，并鉴定循环中与 在GBM动物模型中的脑中具有抗肿瘤活性（目的1）;我们将进行研究性新药 （IND）-使用临床级OV-α CD 47-G1进行体内安全性和有效性研究（目标2）;我们将 确定成人患者单次脑内输注OV-α CD 47-G1的安全性， 复发性GBM（目标3）。为了实现这些目标，我们将利用免疫活性和 免疫功能低下的GBM小鼠模型，用于我们评估OV-α CD 47-G1的相关和临床前研究 在I期临床试验之前。结论是，我们将了解如何优化OV-α CD 47-G1治疗， 治愈GBM进一步深入了解这一进程，将导致执行和完成这一进程， 该提案是有影响力的，因为它最终将导致患有GBM的成年人的死亡率降低。

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.