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: 9796971
• 负责人: Michael R. King
• 金额: $ 3.82万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9796971
• 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; Lymphatic Spread; Lymphatic System; Malignant Epithelial Cell; Malignant Neoplasms; Mesentery; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Modeling; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Organ; 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; cytotoxicity; dosage; efficacy study; efficacy testing; in vivo; innovation; insight; intraperitoneal; lymph nodes; 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 在大多数类型的癌症中，肿瘤引流淋巴结(LN)是转移的首发部位。转移的程度 在LN常用于癌症进展的分期。值得注意的是，在最近的工作中，申请者描述了一种小说 当与人自然杀伤(NK)细胞结合时，纳米TRAIL包衣脂质体增强其 体内和体外杀灭癌细胞的内源性治疗潜力。在这项概念验证研究中， 申请者将通过将这些脂质体与NK细胞结合来靶向LN，并将研究他们的 能够防止小鼠结肠癌肿瘤的淋巴扩散。这将表明，靶向NK细胞 TRAIL脂质体可延长脂质体在区域淋巴结内的滞留时间以诱导细胞凋亡 癌细胞。如果成功，建议的方法可以用来杀死肿瘤引流层内的癌细胞 以防止癌症的淋巴扩散。拟议的工作分为三个具体目标。特定的 目的1：探讨TRAIL/抗NK1.1脂质体的作用机制，并检测其抗肿瘤疗效。 皮下LN转移模型中的耐药结肠癌。次级目标1.1：审查不同组织的作用 自然杀伤细胞受体对超NK细胞的杀伤作用。次级目标1.2：测试TRAIL/抗NK1.1的疗效 用于治疗奥沙利铂耐药结肠癌的脂质体。奥沙利铂是一种临床上重要的铂类药物 然而，奥沙利铂的长期治疗已被证明会导致在 结直肠癌细胞。具体目标2：表征阿昔洛韦的生物分布、药代动力学和毒性 TRAIL/抗NK1.1脂质体腹腔注射。脂质体的腹腔注射途径为 检查以使在AIM 3的原位结肠癌模型中进行疗效研究。子目标2.1：检查 TRAIL/抗NK1.1脂质体的全身生物分布和层粘连蛋白药代动力学 肠系膜淋巴结。次级目标2.2：评估反复注射腹膜后的毒性 注射TRAIL/抗NK1.1脂质体。特异目的3：评价TRAIL/抗NK1.1脂质体在小鼠体内的疗效 结肠癌肠系膜淋巴结转移和脾肝转移的原位模型。子- 目的3.1：评价TRAIL/抗NK1.1脂质体治疗结肠癌原位转移的疗效。 肠系膜淋巴结。次级目标3.2：治疗从脾到肝的继发性转移瘤 静脉注射TRAIL/抗NK1.1脂质体。将结肠癌细胞注射到脾内的一种淋巴管 器官，检查静脉注射TRAIL/抗NK1.1脂质体治疗是否也能预防或减少 从脾到肝的继发性转移。影响：这种创新的基于TRAIL-脂质体的干预 将证明NK细胞可以用来清除肿瘤引流层中的致瘤细胞，从而 防止LN转移的形成，这是目前尚未得到满足的需求。这个项目的成功将建立一个新的 以细胞为基础的受体-配体疗法治疗各种疾病的平台技术 癌症和其他疾病。