Design of a micro-RNA attenuated armed oHSV for the treatment of glioblastoma

用于治疗胶质母细胞瘤的 micro-RNA 减毒武装 oHSV 的设计

基本信息

批准号：
9904963
负责人：
Christophe Queva
金额：
$ 30万
依托单位：
ONCORUS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9904963
关键词：
Acute Antibodies Antigen-Presenting Cells Antitumor Response Attenuated Autologous Brain CCL4 gene CD47 gene CD8-Positive T-Lymphocytes CTLA4 gene Cancer Vaccines Cell Differentiation process Cell Line Cells Clinic Clinical Clinical Trials Coagulation Process Complement Complex Data Dendritic Cells Development Disease Engineering Essential Genes FLT3 ligand Fatal Outcome Future Generations Genes Genetic Genetic Engineering Genetic Models Glioblastoma Goals Head and Neck Squamous Cell Carcinoma Herpesvirus 1 Human Immune Immune response Immune system Immunologics Immunotherapy Injections Interleukin-12 Lead Ligands Malignant - descriptor Malignant Neoplasms Medical Messenger RNA MicroRNAs Microglia Modeling Mus Mutation Myeloid-derived suppressor cells Natural Killer Cells Neoadjuvant Therapy Neurons Oncogenic Viruses Oncolytic Oncolytic viruses Patient-Focused Outcomes Patients Pattern Pre-Clinical Model Research Role SLEB2 gene Safety Signal Transduction Simplexvirus Solid T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Thromboplastin Tissues Transgenes Tumor Antigens Tumor Immunity Tumor-associated macrophages Untranslated RNA Virus Virus Diseases Virus Replication anti-PD-1 anti-PD1 antibodies anti-tumor immune response arm attenuation brain tissue cancer cell cell killing checkpoint inhibition clinical candidate clinical development design differential expression experimental study gene product human disease immune activation improved in vivo individualized medicine inflammatory milieu innovation lead candidate macrophage meetings mouse model neoplastic cell neuronal transport next generation novel novel therapeutic intervention oncolytic herpes simplex virus pre-clinical prevent programs promoter receptor recruit systemic toxicity tumor vector

项目摘要

The most aggressive form of brain malignancies, glioblastoma multiforme (GBM) represents a particularly acute unmet medical need. GBM are highly invasive and do not respond to immune checkpoint inhibition due to their suppressive microenvironment. Oncolytic viruses engineered to selectively replicate and kill malignant GBM cells and to express transgenes that stimulate antitumor immunity are attractive approaches to improve patient outcomes as monotherapy and in combination with anti-PD-1 therapeutics. Preliminary data achieved with a prototypical oncolytic herpes simplex virus (oHSV) armed with ULBP3, a ligand for KLRK1 a stimulatory receptor expressed in CD8 and NK cells and featuring the improvements in oncolytic potency, micro-RNA attenuation and payload capacity designed by Oncorus demonstrated a significant survival benefit after a single intratumoral injection in a genetically inducible model of GBM designed to recapitulate the major genetic alterations and pathobiology of GBM. Moreover, injection of oHSV expressing ULBP3 in one tumor mass resulted in an abscopal anti-tumor response in the uninjected tumor mass. This result was surprising since the human-specific ULBP3 gene product does not recognize the mouse KLRK1 receptor and primarily acts through the recruitment of macrophages and microglia, suggesting a novel receptor for ULBP3 on these cells both in mouse and human. Preliminary studies identified tissue factor, a transmembrane receptor with a role in coagulation and signaling in GBM as this new receptor. We aim to investigate the mode of action of ULBP3 in GBM models and confirm this novel interaction. We propose to further exploit these initial findings for the design of an optimized armed oHSV for the treatment of GBM. As a first step, we will tailor the unique safety features of Oncorus oHSV, the selection of micro-RNA highly expressed in healthy brain tissues and lost in GBM to insert complementary micro-RNA target sequences in multiple genes essential to HSV replication, thus restraining viral replication to malignant cells. MicroRNA 124, 128 and 137 that showed strong differential expression are likely candidates. Additionally, payloads, including IL-12, and PD-1 and CD47 antagonists, that have been validated in GBM preclinical models, and that may complement the activity of ULBP3 will be tested stepwise in GBM cell lines and tumor cells for oncolytic activity, expression and in vivo efficacy in syngeneic GBM models and in state-of-the-art inducible genetic models. From these data the optimized combination of payloads will be introduced into our oHSV in order to create the most potent vector and clinical candidate for future human trials. !

脑恶性肿瘤最具侵略性的形式，胶质母细胞瘤多形（GBM）代表着特别急性的未满足的医疗需求。 GBM具有高度侵入性，并且由于其抑制作用而没有响应免疫检查点抑制性微环境。溶瘤病毒设计为选择性复制和杀死恶性GBM 细胞并表达刺激抗肿瘤免疫力的转基因是改善患者的有吸引力的方法结果作为单一疗法，并与抗PD-1治疗剂结合使用。通过配备ULBP3的原型野疱疹单纯疱疹病毒（OHSV），klrk1的配体刺激受体在CD8和NK细胞中表达，并具有改善溶瘤效力，微RNA衰减由Oncorus设计的有效载荷能力表现出单个肿瘤后的显着生存益处在旨在概括主要遗传改变和的GBM遗传诱导模型中注射 GBM病理生物学。此外，在一个肿瘤质量中注射OHSV表达ULBP3导致潜流未注入的肿瘤质量中的抗肿瘤反应。由于人类特异性的ULBP3，该结果令人惊讶基因产物不识别小鼠KLRK1受体，主要通过募集起作用巨噬细胞和小胶质细胞，表明在小鼠和人类中，这些细胞上的ULBP3新型受体。初步研究确定了组织因子，这是一种在凝结和信号中作用的跨膜受体 GBM作为这个新受体。我们旨在研究GBM模型中ULBP3的作用方式，并确认这一点新颖的互动。我们建议进一步利用这些初始发现来设计优化的武装OHSV 用于治疗GBM。作为第一步，我们将量身定制Oncorus OHSV的独特安全功能（选择）在健康脑组织中高度表达的微RNA，在GBM中丢失以插入互补的微RNA 对HSV复制必不可少的多个基因中的靶序列，从而将病毒复制限制为恶性肿瘤细胞。显示出强差异表达的microRNA 124、128和137可能是候选者。此外，在GBM临床前模型中已验证的有效载荷，包括IL-12，PD-1和CD47拮抗剂，这可能会补充ULBP3的活性将在GBM细胞系和肿瘤细胞中逐步测试溶瘤活性，表达和体内疗效以及最先进的诱导性遗传模型。从这些数据中，有效载荷的优化组合将引入我们的OHSV 为了创建最有效的向量和未来人类试验的临床候选者。呢