Development of Natural Killer (NK) Cell Line-Derived Extracellular Vesicles as a New Treatment for Cancer

开发自然杀伤 (NK) 细胞系衍生的细胞外囊泡作为癌症的新治疗方法

基本信息

批准号：
10383462
负责人：
JACKI KORNBLUTH
金额：
$ 39.96万
依托单位：
VANQUISH BIO LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10383462
关键词：
ADME Study Allogenic Autologous Behavior Blood - brain barrier anatomy Blood Chemical Analysis Body Weight Bone Pain Cell Count Cell Death Cell Line Cell Proliferation Cell Therapy Cells Cessation of life Characteristics Chemoresistance Clinical Research Clinical effectiveness Combined Modality Therapy Control Groups Data Development Diagnosis Disease Disease remission Freezing Future Generations Goals Growth Healthcare Hematologic Neoplasms Hematopoietic Histocompatibility Hospital Referrals Hour Human Immune system Immunodeficient Mouse Immunohistochemistry Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Infusion procedures Interleukin-12 Interleukin-15 Interleukin-2 Kidney Knowledge Laboratories Lead Managed Care Programs Measures Medical Oncologist Membrane Metabolic Modality Modeling Multiple Myeloma Mus Natural Killer Cells Natural Products Neoplasm Metastasis Normal Cell Organ Organ Weight Outcome Pain Particle Size Patients Pharmaceutical Preparations Phase Preparation Primary Health Care Production Proteins RNA Recurrence Refractory Refractory Disease Relapse Residual Neoplasm Resistance Route Sales Small Business Technology Transfer Research Stable Disease Stem cell transplant Structure Survival Rate Symptoms Testing Therapeutic Tissues Toxic effect Variant blood group cancer cell cancer stem cell cancer therapy cancer type cell killing chemotherapy cohort commercial application cytokine cytokine release syndrome experimental group extracellular vesicles graft vs host disease human model improved innovation loss of function mouse model nanoparticle neoplastic cell patient advocacy group pre-clinical prevent protein expression side effect technological innovation tertiary care tumor tumor hypoxia tumor microenvironment

项目摘要

Vanquish Bio is an immunotherapy company reimagining treatment of cancer with the use of unique natural killer (NK) cell derived extracellular vesicles (EVs). The goal of this STTR is to develop a therapy using natural products of the immune system for targeted destruction of myeloma tumor cells. Multiple myeloma (MM) represents ~10% of hematological cancers, and there were ~32,110 new cases and ~12,960 deaths in the U.S. in 2019. Despite treatments that include stem cell transplantation and/or chemotherapy, patients inevitably relapse. New innovations are needed that extend survival, increase durability of remission and provide options to patients ineligible for front-line therapy. We developed NK3.3, a human NK cell line derived from a healthy donor. These cells kill an array of tumor types. Using a minimal residual disease mouse model of human MM, administration of NK3.3 EVs prevented tumor recurrence for up to 100 days, versus 21 days without treatment. As NK3.3 grow in culture, they release EVs as small membrane-bound structures that are also capable of killing many different tumor cells without harming normal cells. NK3.3 EVs also kill cancer stem cells (CSC); these are resistant to standard chemotherapy and responsible for metastasis and recurrence. NK EVs can be produced in large quantities, frozen, stored and then thawed, without loss of function. Other advantages of using NK3.3 EVs include: 1) resistance to the hypoxic tumor microenvironment, 2) ability to cross the blood-brain barrier, 3) stability and 4) low toxicity. EVs are not restricted by blood group or histocompatibility and are therefore an immunotherapeutic modality that can be a universal treatment. Our goal is to develop a new infusion therapy product that will improve survival rates with less side effects for MM patients with relapsed/refractory or stable disease. Phase I is to generate NK3.3-derived EVs and demonstrate efficacy against MM and extend durability of remission, with minimal, toxic side effects. Specific Aim 1: Identify activators that maximize tumor killing activity of NK3.3 EVs. NK EVs will be isolated from NK3.3 cells cultured with activating cytokines IL-2, IL-12 and IL-15 individually and in combinations. Our goal is to prepare NK EVs that kill ≥90% of tumor cells within 72 hours of treatment, with less than 10% normal cell death. Specific Aim 2: Determine proof-of-concept efficacy with low toxicity of NK EVs in MM-bearing immunodeficient mice. We will administer different concentrations of NK EVs in MM-bearing immunodeficient mice with stable disease. The goal is to extend remission beyond 21 days in ≥50% of mice. Toxicity will be measured for qualitative visible signs and behavior, and quantitative variation in body weight, organ weight and blood chemistry. We will prove feasibility of producing more potent NK EV preparations with anti-MM activity and proof-of-concept oriented efficacy and toxicity data of NK EV therapy against MM.

Vanquish Bio是一家免疫疗法公司，使用独特的天然来重新构想癌症治疗杀手（NK）细胞衍生出细胞外蔬菜（EV）。该STTR的目的是使用天然开发一种疗法免疫系统的产物靶向骨髓瘤肿瘤细胞的靶向破坏。多发性骨髓瘤（mm）约占血液学癌的约10％，〜32,110例新病例，约有12,960例死亡美国在2019年。尽管治疗包括干细胞移植和/或化学疗法，但患者不可避免地会中继。需要进行新的创新，以扩大生存，增加缓解耐用性和为不符合前线治疗的患者提供选择。我们开发了NK3.3，这是一种人类NK细胞系来自健康的捐助者。这些细胞杀死了一系列肿瘤类型。使用最小残留疾病小鼠模型人类MM的施用NK3.3 EV可预防长达100天的肿瘤复发，而21天没有治疗。随着NK3.3在文化中的增长，它们以膜结合的小结构释放EV 也能够杀死许多不同的肿瘤细胞而不会损害正常细胞。 NK3.3电动汽车也杀死了癌症细胞（CSC）;这些对标准化疗具有抗性，并负责转移和复发。 NK 电动汽车可以大量生产，冷冻，储存和融化，而不会损失功能。其他使用NK3.3 EV的优点包括：1）对低氧肿瘤微环境的抗性，2）越过血脑屏障，3）稳定性和4）低毒性。电动汽车不受血液组的限制或组织相容性，因此是一种免疫治疗方式，可以是普遍治疗。我们的目标是开发一种新的输注疗法，该产品将提高生存率，而MM的副作用较小继电器/难治性或稳定疾病的患者。第一阶段将生成NK3.3衍生的电动汽车，并证明针对MM的效率并扩展耐用性缓解，具有最小的有毒副作用。特定目标1：确定最大化NK3.3 EV肿瘤活性的激活剂。 NK EV会用活化细胞因子IL-2，IL-12和IL-15分离从NK3.3细胞分离组合。我们的目标是准备NK EVS，该EV在治疗的72小时内杀死≥90％的肿瘤细胞，并在小于正常细胞死亡的10％。特定目标2：确定MM含量低的NK EV毒性的概念验证效率免疫缺陷小鼠。我们将在承担MM的免疫缺陷中管理不同浓度的NK EV 患有稳定疾病的小鼠。目标是在≥50％的小鼠中将缓解延伸到21天以上。毒性将是用于定性可见的迹象和行为，以及体重，器官重和体重的定量变化血液化学。我们将证明具有抗MM活性产生更多潜在的NK EV制剂的可行性 NK EV疗法针对MM的概念证明效率和毒性数据。