Development of Immunostimulatory Virotherapy Without Neurotoxicity for the Treatment of Brain Malignancies

开发无神经毒性的免疫刺激病毒疗法治疗脑恶性肿瘤

基本信息

批准号：
10323138
负责人：
Matthew Stremlau
金额：
$ 39.93万
依托单位：
IMPLICYTE, INC.
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：
2021-09-10 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323138
关键词：
Animal Model Animals Biological Assay Biological Products Brain Brain Neoplasms Businesses CD40 Ligand Cancer cell line Cell Culture Techniques Cell membrane Cells Chikungunya virus Classification Clinical Clinical Trials Complex Cytolysis Development Diagnosis Dose Drug Design Engineering Ensure Excision Future Glioblastoma Glioma Glycoproteins Goals Heterogeneity Human Immune Immune system Immunocompetent Immunologic Memory Immunologics Immunotherapy In Vitro Infiltration Interleukin-12 Lassa virus Lead Malignant - descriptor Malignant Neoplasms Measures Mediating Membrane Modality Modernization Mus Mutation Neoplasm Metastasis Neurons Oncolytic Oncolytic viruses Operative Surgical Procedures Patients Phase Polysaccharides Primary Brain Neoplasms Proteins Radiation Recombinants Rights Safety Secure Small Business Innovation Research Grant Solid Neoplasm Testing Therapeutic Time Toxic effect Transgenes Treatment Efficacy Universities Vesicular stomatitis Indiana virus Virotherapy Virus anti-tumor immune response arm base brain tissue cancer therapy cancer type chemotherapy clinical candidate cytotoxicity drug development efficacy evaluation experience immune clearance immunogenicity improved in vivo innovation medical schools mouse model neoplastic cell neurosurgery neurotoxicity neurotropic neutralizing antibody novel novel therapeutics novel virus oncolytic virotherapy phase 2 study preclinical study prevent professor recombinant virus research and development response screening standard of care success therapeutic candidate transgene expression tumor tumor eradication tumor-immune system interactions

项目摘要

PROJECT SUMMARY Glioblastoma is one of the most lethal and recalcitrant of all malignant solid tumors. Treatment modalities have not improved significantly in two decades. Glioblastoma is difficult to treat because of its inherent heterogeneity, a low mutational load that reduces its intrinsic immunogenicity, and a highly immunosuppressive microenvironment that prevents infiltration by critical immune cells. Although immunotherapy has transformed modern cancer treatment, patients with glioblastoma have generally not demonstrated strong or durable responses, leading to the classification of glioblastoma as an immunologically ‘cold’ tumor. Novel therapies that can augment immunotherapy and enhance the anti-tumor immune response are urgently needed. Oncolytic virotherapy is a novel platform for treating brain malignancies and potentiating tumors that respond poorly to standard therapeutic approaches, including immunotherapy. Recombinantly-modified oncolytic viruses permit a multifaceted and synergistic therapeutic drug design approach that directly destroys the tumor through targeted lysis, while also expressing immunostimulatory transgenes in a complementary manner that enhance immune-mediated tumor eradication. Implicyte, Inc. has developed two non-neurotoxic chimeric vesicular stomatitis viruses (VSV) that selectively infect and destroy glioblastoma cells, but not normal brain tissue. This virotherapy platform features several key innovations: it is non-neurotoxic and safe for use in the brain; it can be further engineered to express multiple immunostimulatory transgenes; it has the ability to destroy secondary tumors in the brain; it can evade neutralizing antibodies allowing for re-dosing; and it can target multiple cancer types. Here we propose to further advance our novel non-neurotoxic chimeric VSVs by engineering them to express immunostimulatory transgenes that will significantly enhance the anti- tumor immune response. In Specific Aim 1, we will further improve Implicyte’s chimeric VSV viruses by ‘arming’ them with two immunostimulatory transgenes. These novel viruses will be validated using in vitro cell culture assays to ensure they replicate as well as the parental viruses, are non-toxic to primary human neurons, and express the immunostimulatory transgenes at high levels. In Specific Aim 2, we will use in vivo syngeneic mouse models to evaluate the efficacy and immunostimulatory enhancement of these viruses. In these in vivo studies, we expect expression of the immunostimulatory transgenes to accelerate elimination of the tumor, improve overall survival, and induce immunological memory in mice challenged with a second tumor. Once this study is complete, we will have a lead clinical candidate that can be advanced to Phase II-supported IND-enabling studies to secure approval for future clinical trials. Implicyte’s non-neurotoxic oncolytic virotherapy, which combines direct tumor lysis with an anti-tumor immune response, has the potential to not only eradicate a patient’s tumor, but prevent its reoccurrence aswell.

项目概要胶质母细胞瘤是所有恶性实体瘤中最致命和最顽固的一种。胶质母细胞瘤由于其固有的异质性而难以治疗，低突变负荷降低了其内在的免疫原性，并且高度免疫抑制尽管免疫疗法已经发生了变化，但阻止关键免疫细胞渗透的微环境。现代癌症治疗中，胶质母细胞瘤患者通常没有表现出强大或持久的反应，导致胶质母细胞瘤被归类为免疫学“冷”肿瘤。迫切需要能够增强免疫治疗并增强抗肿瘤免疫反应的药物。溶瘤病毒疗法是一种治疗脑恶性肿瘤和增强肿瘤反应的新平台标准治疗方法（包括重组改良溶瘤疗法）效果不佳。病毒允许采用多方面、协同的治疗药物设计方法，直接破坏肿瘤通过靶向裂解，同时还以互补的方式表达免疫刺激转基因 Implicyte, Inc. 开发了两种非神经毒性嵌合体增强免疫介导的肿瘤根除。水泡性口炎病毒 (VSV)，选择性感染并破坏胶质母细胞瘤细胞，但不影响正常细胞该病毒治疗平台具有多项关键创新：无神经毒性且使用安全。在大脑中；它可以被进一步改造以表达多种免疫刺激转基因；破坏大脑中的继发性肿瘤；它可以逃避中和抗体，从而允许重新给药；在这里，我们建议进一步推进我们的新型非神经毒性嵌合体。 VSV 通过工程化使其表达免疫刺激转基因，从而显着增强在具体目标1中，我们将进一步改进Implicyte的嵌合VSV病毒。通过用两种免疫刺激转基因“武装”它们，这些新型病毒将在体外得到验证。细胞培养测定确保它们与亲代病毒一样复制，对原代人类无毒神经元，并高水平表达免疫刺激转基因。在具体目标 2 中，我们将在体内使用。同基因小鼠模型来评估这些病毒的功效和免疫刺激增强作用。这些体内研究，我们期望免疫刺激转基因的表达能够加速消除肿瘤，提高总体生存率，并诱导接受第二次攻击的小鼠的免疫记忆一旦这项研究完成，我们将拥有一个可以进入临床阶段的主要临床候选药物。 II 支持 IND 启用研究，以确保 Implicyte 的非神经毒性临床试验获得批准。溶瘤病毒疗法将直接肿瘤溶解与抗肿瘤免疫反应相结合，具有潜力不仅可以根除患者的肿瘤，还可以防止其复发。