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

• 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
• 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

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是一家免疫治疗公司，利用独特的天然药物， 杀伤（NK）细胞衍生的细胞外囊泡（EV）。该STTR的目标是开发一种使用天然药物的治疗方法， 用于骨髓瘤肿瘤细胞的靶向破坏的免疫系统的产物。多发性骨髓瘤（MM） 占血液系统癌症的约10%，其中约32，110例新发病例和约12，960例死亡。 美国2019年尽管治疗包括干细胞移植和/或化疗， 不可避免地复发。需要新的创新来延长生存期，增加缓解的持久性， 为不符合一线治疗条件的患者提供选择。我们开发了NK 3.3，一种人类NK细胞系， 一个健康的捐赠者这些细胞杀死一系列肿瘤类型。使用微小残留病小鼠模型 在人MM中，施用NK3.3 EV预防肿瘤复发长达100天，而不是21天。 没有治疗。当NK3.3在培养物中生长时，它们释放EV作为小的膜结合结构， 也能够杀死许多不同的肿瘤细胞而不伤害正常细胞。NK3.3电动汽车也能杀死癌症干细胞 细胞（CSC）;这些细胞对标准化疗有抗性，并导致转移和复发。NK 电动汽车可以大量生产，冷冻，储存，然后解冻，而不会失去功能。其他 使用NK3.3EV的优点包括：1）对缺氧肿瘤微环境的抗性，2） 穿过血脑屏障，3）稳定性和4）低毒性。电动汽车不受血型或 组织相容性，因此是一种可以作为通用治疗的免疫疗法。我们的目标 是开发一种新的输液治疗产品，将提高生存率，减少副作用的MM 复发性/难治性或稳定性疾病患者。 I期是产生NK3.3衍生的EV，并证明对MM的疗效和延长 缓解，最小的毒副作用。 具体目标1：鉴定使NK3.3 EV的肿瘤杀伤活性最大化的活化剂。NK EV将成为 分离自分别用活化细胞因子IL-2、IL-12和IL-15培养的NK 3.3细胞， 组合。我们的目标是制备在治疗72小时内杀死≥90%肿瘤细胞的NK EV， 少于10%的正常细胞死亡。 具体目标2：确定NK EV在MM携带者中的低毒性概念验证疗效 免疫缺陷小鼠我们将在携带MM的免疫缺陷小鼠中施用不同浓度的NK EV。 病情稳定的小鼠。目标是在≥50%的小鼠中将缓解期延长至21天以上。毒性将是 测量定性可见体征和行为，以及体重、器官重量和 血液化学我们将证明生产具有抗MM活性的更有效的NK EV制剂的可行性 以及针对MM的NK EV疗法的概念验证导向的功效和毒性数据。