Off-the-shelf engineered NK cells to treat glioblastoma

现成的工程 NK 细胞用于治疗胶质母细胞瘤

• 批准号: 10481503
• 负责人: Joe Trebley
• 金额: $ 39.93万
• 依托单位: MONON BIOVENTURES, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10481503
• 关键词: Address; Adoptive Transfer; Adult; Antibody Therapy; Antitumor Response; Autologous; Blood; Blood Cells; Brain; CAR T cell therapy; CD94 Antigen; Cell Degranulation; Cell Therapy; Cells; Childhood; Clinic; Clinical; Collaborations; Combination Drug Therapy; Cyclic GMP; DNA; Data; Defense Mechanisms; Detection; Diagnosis; Disease; Disease Outcome; Engineering; Feedback; Funding; Gene Expression; Glioblastoma; Goals; Heterogeneity; Human Engineering; Immune; Immune Evasion; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Lentivirus Vector; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methods; Mind; Modeling; Molecular Weight; Mus; NK cell therapy; Natural Killer Cells; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Persons; Phase; Production; Radiation therapy; Recurrence; Reporting; Source; Survival Rate; T-Lymphocyte; Tail; Testing; Therapeutic; Treatment Efficacy; Treatment outcome; Umbilical Cord Blood; Universities; Work; Xenograft Model; Xenograft procedure; base; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytotoxicity; design; effective therapy; engineered NK cell; engineered T cells; graft vs host disease; immunoengineering; improved; improved outcome; in vivo; innovation; meetings; mouse model; nature therapy; novel; peripheral blood; phase I trial; pre-clinical; receptor expression; response; side effect; standard of care; success; therapy resistant; transduction efficiency; treatment group; tumor; tumor growth; tumor-immune system interactions; vaccine-induced antibodies; vector

PROJECT SUMMARY Glioblastoma (GBM) is the most lethal form of brain cancer and more than 12,000 people are diagnosed with this disease every year. Current standard of care involved surgery where possible, followed by a combination of chemotherapy and radiotherapy. Unfortunately, the outcome of treatment remains poor with only 15% of patients surviving beyond 5 years. Recent advances in immunotherapy, such as CAR-T cell therapy, have been promising with other cancers but numerous studies have identified several hurdles in applying these methods effectively to glioblastoma. Particularly, GBM cells have high heterogeneity allowing them to escape immune detection, and they present an immunosuppressive microenvironment which reduces the efficacy of immunotherapies. Moreover, the engineered T cells are challenging to source as they elicit a strong graft-vs- host disease response. Monon Bioventures, in collaboration with Dr. Matosevic at Purdue University, is developing an immunotherapy that addresses the limitations of previous approaches. We have designed a novel triple-specific CAR-NK cell capable of overcoming these hurdles through multiple specific mechanisms – improved tumor infiltration and locally-responsive targeted activity while overcoming multiple mechanisms of immunosuppression. Additionally, NK cells do not require stringent donor-recipient matching and can be obtained off-the-shelf. Preliminary studies with the triple-specific CAR-NK cells show efficient killing of GBM cells in vitro. Further, in vivo studies with GBM xenografted mice show increased tumor infiltration, reduction in tumor growth and improved survival. Monon Bioventures is bringing this promising therapy from the lab to the clinic. To achieve this goal, we propose to develop a scalable method to produce the CAR-NK cells using NK cells sourced from blood and demonstrate the efficacy of the therapeutic in a GBM xenograft model. The following Specific Aims are planned: Aim 1. Engineer and characterize NK cells isolated from cord blood. This will be carried out through two sub-tasks: Aim 1 A. Recreate the novel lentiviral vector designed by Dr. Matosevic in a GMP-capable facility, validating vector production through scalable methods that are consistent with cGMP standards. Aim 1B. Isolate and transduce NK cells from cord blood; determine transduction efficiency and characterize functionality of the CAR-NK cells. Aim 2. Demonstrate efficacy of CAR-NK in a patient-derived GBM xenograft mouse model. This project will generate the results needed for a Type B Pre-IND meeting with the FDA. With feedback from the FDA, Phase II funding will go to support the IND package necessary to begin the Phase I trial. Once developed, our novel CAR-NK based therapy has the potential to establish a much-needed new standard of care for those suffering from GBM and could significantly improve the outcome of the disease.

项目摘要 胶质母细胞瘤（GBM）是最致命的脑癌形式，超过12，000人被诊断患有 每年都有这种疾病。目前的标准治疗包括手术（如果可能），然后结合 化疗和放疗。不幸的是，治疗结果仍然很差，只有15%的患者 存活超过5年。免疫疗法的最新进展，如CAR-T细胞疗法，已经被广泛应用。 但许多研究已经确定了应用这些方法的几个障碍 有效地治疗胶质母细胞瘤。特别地，GBM细胞具有高异质性，使得它们能够逃避免疫刺激。 检测，它们提供了一种免疫抑制微环境，降低了 免疫疗法此外，工程化T细胞的来源具有挑战性，因为它们引起强烈的移植物抗肿瘤活性。 宿主疾病反应。莫农生物公司与普渡大学的马托塞维奇博士合作， 开发一种免疫疗法，解决以前方法的局限性。我们设计了一部小说 三特异性CAR-NK细胞能够通过多种特异性机制克服这些障碍- 改善的肿瘤浸润和局部反应性靶向活性，同时克服了 免疫抑制此外，NK细胞不需要严格的供体-受体匹配，并且可以被移植。 现成的三特异性CAR-NK细胞的初步研究显示了对GBM细胞的有效杀伤 体外此外，用GBM异种移植小鼠的体内研究显示增加的肿瘤浸润，肿瘤浸润的减少，以及肿瘤细胞的增殖。 增长和提高生存率。莫农生物公司正在将这种有前途的疗法从实验室带到临床。 为了实现这一目标，我们建议开发一种可扩展的方法来使用NK细胞生产CAR-NK细胞 来源于血液，并在GBM异种移植模型中证明治疗剂的功效。以下 计划了具体目标：目标1。设计和表征从脐带血中分离的NK细胞。这将是 通过两个子任务执行：目标1A。在一个新的慢病毒载体中重建Matosevic博士设计的新型慢病毒载体。 具有GMP能力的设施，通过符合cGMP的可扩展方法验证载体生产 标准目标1B。从脐带血中分离和扩增NK细胞;测定转导效率， 表征CAR-NK细胞的功能性。目标2.证明CAR-NK在患者源性GBM中的疗效 异种移植小鼠模型。本项目将生成B类IND前会议所需的结果， FDA.根据FDA的反馈，II期资金将用于支持开始 一期试验。一旦开发出来，我们基于CAR-NK的新疗法有可能建立一种急需的治疗方法。 新的护理标准，为那些患有GBM，并可以显着改善疾病的结果。