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)和单抗(MAb)联合免疫治疗有很大的临床应用价值。 治疗胶质母细胞瘤(GBM)的潜力，这是最常见的无法治愈的恶性脑瘤。一个 携带单抗编码基因的OV可以安全地在肿瘤部位产生和释放单抗药物， 有效的、创新的交付系统。在我们的研究之前，这种方法以前从未被探索过 使用单纯疱疹病毒1型卵泡病毒(OHSV)。CD47是一种在癌症上广泛表达的跨膜蛋白 细胞包括基底膜。它通过作为信号调节蛋白-α的配基发挥作用，从而起到“不要吃我”的信号作用 (Sirpα)在巨噬细胞上表达，导致吞噬功能抑制。我们已经产生了一种OHSV 在免疫球蛋白1支架(OV-αCD47-G1)上表达全长抗CD47mAb，能够诱导抗体- 巨噬细胞的依赖细胞吞噬作用(ADCP)和抗体依赖的细胞杀伤作用(ADCC) 由自然杀伤细胞在体外和体内清除基底膜细胞，除了阻断CD47Sirpα外，还不能 巨噬细胞中的“吃我”信号通路。我们已经证明我们的新OV-αCD47-G1显著地 改善原位、免疫活性和免疫缺陷模型中携带GBM的小鼠的存活率。我们的 中心假说是OV-αCD47-G1将安全有效地改善基底膜的治疗及其抗肿瘤作用。 大脑中的肿瘤活动将通过外周血液中的标志物来反映。重要的是，我们已经优化了 和制造的GMP级OV-αCD47-G1来进行拟议的研究，并将启动I期临床 对患有GBM的成年人的试验。在这项建议中，我们将评估全身和局部免疫反应在 临床级别OV-αCD47-G1后的体内应用并确定循环中相关的标志物 在GBM动物模型中具有抗肿瘤活性(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)；我们将 确定OV-αCD47-G1单次脑内输注治疗成人非霍奇金淋巴瘤的安全性 复发性基底膜(目标3)。为了实现这些目标，我们将利用免疫活性和 用于OV-αCD47-G1相关和临床前研究的免疫缺陷小鼠模型 在I期临床试验之前。通过总结，我们将了解如何优化OV-αCD47-G1治疗以 治愈GBM。进一步洞察这一进程，这将是实施和完成这一进程的结果 这项提议是有影响的，因为它最终将导致患有基底膜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.