Super Natural Killer Cells That Target Metastases in the Tumor-Draining Lymph Nodes

针对肿瘤引流淋巴结转移的超级自然杀伤细胞

• 批准号: 10057356
• 负责人: Michael R. King
• 金额: $ 40.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-23 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057356
• 关键词: Address; Apoptosis; Biodistribution; Cancer Model; Cecum; Cells; Clinical; Colon; Colon Carcinoma; Colorectal Cancer; Diagnostic Neoplasm Staging; Disease; Drug Kinetics; Drug resistance; Effectiveness; Event; Fluorouracil; Formulation; Human; Implant; In Vitro; Inguinal lymph node group; Injections; Intervention; Intraperitoneal Injections; Intravenous; Knowledge; Leucovorin; Ligands; Liposomes; Liver; Lymph Node Tissue; Lymphatic Spread; Lymphatic System; Malignant Epithelial Cell; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Modeling; Molecular; Mus; Natural Killer Cell toxicity; Natural Killer Cells; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phenotype; Platinum; Primary Neoplasm; Prognostic Factor; Property; Proteins; Receptor Cell; Resistance; Role; Route; SW620; Site; Spleen; Subcutaneous Injections; TNFSF10 gene; Technology; Testing; Therapeutic; Time; Toxic effect; Work; Xenograft Model; base; bioluminescence imaging; cancer cell; cancer type; chemotherapy; clinically relevant; colon cancer metastasis; dosage; draining lymph node; efficacy study; efficacy testing; in vivo; innovation; insight; intraperitoneal; lymph nodes; lymphoid organ; mesenteric lymph node; nanoscale; non-invasive monitor; novel; oxaliplatin; prevent; receptor; response; subcutaneous; success; systemic toxicity; targeted treatment; tumor; tumor progression; tumorigenic; uptake

Project Summary/Abstract Tumor-draining lymph nodes (LN) are the first site of metastasis in most types of cancer. The extent of metastasis in the LN is often used in staging cancer progression. Notably, in recent work the applicants described novel nanoscale TRAIL-coated liposomes that when conjugated to human natural killer (NK) cells enhance their endogenous therapeutic potential in killing cancer cells both in vitro and in vivo. In this proof-of-concept study, the applicants will target these liposomes to the LN by conjugating them to NK cells, and will investigate their ability to prevent the lymphatic spread of colon cancer tumors in mice. It will be shown that targeting NK cells with TRAIL liposomes can enhance liposome retention time within regional lymph nodes to induce apoptosis in cancer cells. If successful, the proposed approach could be used to kill cancer cells within the tumor draining LN to prevent the lymphatic spread of cancer. The proposed work is organized into three Specific Aims. Specific Aim 1: To examine the mechanism of TRAIL/Anti-NK1.1 liposome therapy and test their efficacy against drug- resistant colon carcinoma in a subcutaneous LN metastasis model. Sub-aim 1.1: Examine the roles of different natural killer cell receptors on super NK cytotoxicity. Sub-aim 1.2: To test the efficacy of TRAIL/Anti-NK1.1 liposomes to treat oxaliplatin-resistant colon cancer. Oxaliplatin is a clinically important platinum-based drug however long-term treatments with oxaliplatin have been shown to lead to the acquisition of drug resistance in colorectal cancer cells. Specific Aim 2: To characterize the biodistribution, pharmacokinetics and toxicity of TRAIL/Anti-NK1.1 liposomes introduced intraperitoneally. Intraperitoneal route of liposome injection will be examined to enable efficacy studies in the orthotopic colon cancer model of Aim 3. Sub-aim 2.1: To examine the whole body biodistribution and LN pharmacokinetics of TRAIL/Anti-NK1.1 liposomes, with special focus on the mesenteric lymph nodes. Sub-aim 2.2: To assess for toxicity in response to repeated intraperitoneal injections of TRAIL/Anti-NK1.1 liposomes. Specific Aim 3: To evaluate TRAIL/Anti-NK1.1 liposome efficacy in an orthotopic model of colon cancer metastasis to the mesenteric lymph nodes and spleen-to-liver metastasis. Sub- aim 3.1: Characterize the efficacy of TRAIL/Anti-NK1.1 liposomes to treat orthotopic colon cancer metastasis to the mesenteric lymph nodes. Sub-aim 3.2:Treatment of secondary metastasis from the spleen to the liver with intravenous TRAIL/Anti-NK1.1 liposomes. Colon carcinoma cells will be injected into the spleen, a lymphatic organ, to examine whether intravenous TRAIL/Anti-NK1.1 liposome treatment can also prevent or reduce secondary metastasis from the spleen to the liver. IMPACT: This innovative TRAIL-liposome based intervention will demonstrate that NK cells can be used to eliminate tumorigenic cells in the tumor-draining LN, and thus prevent the formation of LN metastases, a currently unmet need. The success of this project will establish a new platform technology for the cellular-based delivery of receptor-ligand therapeutics for the treatment of various cancers and other diseases.

项目摘要/摘要 肿瘤淋巴结（LN）是大多数类型癌症的第一个转移部位。转移的程度 在LN中，通常用于分期癌症进展。值得注意的是，在最近的工作中，申请人描述了新颖 与人类天然杀手（NK）结合时，纳米级尾涂的脂质体会增强其 内源性治疗潜力在体外和体内杀死癌细胞。在这项概念验证研究中， 申请人将通过将这些脂质体连接到NK细胞，将这些脂质体靶向LN，并将调查其 预防小鼠结肠癌肿瘤淋巴扩散的能力。会显示靶向NK单元 伴随着脂质体可以增强区域淋巴结内的脂质体保留时间，以诱导细胞凋亡 癌细胞。如果成功，则建议的方法可用于杀死肿瘤排出的LN癌细胞 为了防止癌症的淋巴扩散。拟议的工作分为三个特定目标。具体的 目的1：检查TRAIL/抗NK1.1脂质体疗法的机制，并测试其对药物的功效 皮下LN转移模型中的抗性结肠癌。 Sub-aim 1.1：检查不同的角色 超级NK细胞毒性上的天然杀伤细胞受体。 Sub-aim 1.2：测试步道/抗NK1.1的功效 脂质体治疗耐药结肠癌。奥沙利铂是一种临床上重要的基于铂的药物 但是，已经证明用奥沙利铂的长期治疗可导致获得耐药性 结直肠癌细胞。特定目的2：表征生物分布，药代动力学和毒性 TRAIL/抗NK1.1脂质体腹膜内引入。脂质体注射的腹膜内途径将是 检查以在目标的原位结肠癌模型3。Sub-aim 2.1中启用功效研究：检查 整个身体的生物分布和LN径向/抗NK1.1脂质体的药代动力学，特别关注 肠系膜淋巴结。 Sub-aim 2.2：评估响应重复腹膜的毒性 注射小径/抗NK1.1脂质体。特定目的3：评估TRAIL/ANTII-NK1.1脂质体功效 结肠癌转移到肠系膜淋巴结和脾向肝转移的原位模型。亚 AIM 3.1：表征TRAIL/anti-NK1.1脂质体的疗效将原位结肠癌转移治疗为 肠系膜淋巴结。 Sub-aim 3.2：处理从脾脏到肝脏的继发转移 静脉径径/抗NK1.1脂质体。结肠癌细胞将被注入脾脏，淋巴 器官，检查静脉径径/抗NK1.1脂质体处理是否也可以防止或减少 从脾脏到肝脏的继发转移。影响：这种创新的基于脂质体的干预 将证明NK细胞可用于消除肿瘤排出的LN中的肿瘤细胞，从而消除 防止形成LN转移，这是当前未满足的需求。该项目的成功将建立一个新的 用于基于细胞的受体配体治疗剂的平台技术，用于治疗各种 癌症和其他疾病。

项目成果

Circulating prostate cancer cells have differential resistance to fluid shear stress-induced cell death.

• DOI: 10.1242/jcs.251470
• 发表时间: 2021-02-22
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Hope JM;Bersi MR;Dombroski JA;Clinch AB;Pereles RS;Merryman WD;King MR
• 通讯作者: King MR

Mechanosensitive Ion Channels: TRPV4 and P2X7 in Disseminating Cancer Cells.

• DOI: 10.1097/ppo.0000000000000312
• 发表时间: 2018
• 期刊: Cancer journal (Sudbury, Mass.)
• 作者: Hope JM;Greenlee JD;King MR
• 通讯作者: King MR

Micelle-in-Liposomes for Sustained Delivery of Anticancer Agents That Promote Potent TRAIL-Induced Cancer Cell Apoptosis.

• DOI: 10.3390/molecules26010157
• 发表时间: 2020-12-31
• 期刊: Molecules (Basel, Switzerland)
• 作者: Zhang Z;Patel SB;King MR
• 通讯作者: King MR

Piezo1 Mechano-Activation Is Augmented by Resveratrol and Differs between Colorectal Cancer Cells of Primary and Metastatic Origin.

• DOI: 10.3390/molecules27175430
• 发表时间: 2022-08-25
• 期刊: Molecules (Basel, Switzerland)

Nanomaterials for the Capture and Therapeutic Targeting of Circulating Tumor Cells.

• DOI: 10.1007/s12195-017-0497-4
• 发表时间: 2017
• 期刊: Cellular and molecular bioengineering
• 影响因子: 2.8
• 作者: Zhang Z;King MR
• 通讯作者: King MR