Assessing the effect of anti-PD-1/PD-L1 agents on tumoricidal efficacy of secretory TRAIL-armed NK cells

评估抗 PD-1/PD-L1 药物对分泌性 TRAIL 武装 NK 细胞的杀肿瘤功效的影响

基本信息

批准号：
9228738
负责人：
YONG J LEE
金额：
$ 7.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-12 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9228738
关键词：
Antibodies Antineoplastic Agents Antitumor Response Apoptosis Applications Grants Biological Blocking Antibodies Brain Cause of Death Cell Therapy Cells Cessation of life Clinical Trials Coculture Techniques Combined Modality Therapy Disease Distant Distant Metastasis Drug Kinetics Effectiveness Growth Half-Life Immunotherapeutic agent Immunotherapy Incidence Injectable Intravenous Bolus Lesion Ligands Liver Lung Malignant Neoplasms Melanoma Cell Metastatic Melanoma Modeling Morbidity - disease rate Mus Natural Killer Cells Neoplasm Metastasis Normal Cell Operative Surgical Procedures Outcome Study Pathway interactions Patients Proteins Radiation therapy Recombinants Regimen Serum Signal Transduction Site Skin Cancer System TNF gene Testing Toxic effect Work Xenograft Model Xenograft procedure advanced disease antitumor effect base bone cancer therapy chemotherapy combinatorial cytokine cytotoxic cytotoxicity improved killings lymph nodes melanocyte melanoma mortality mouse model neoplastic cell novel preclinical efficacy skin color treatment effect tumor tumor xenograft

项目摘要

ABSTRACT Melanoma is a serious form of skin cancer that develops in skin color cells (melanocytes). When melanomas progress to an advanced stage, treatment options are limited and are associated with significant morbidity and mortality. In this grant application, we propose to develop a combinatorial immunotherapy to treat metastatic melanoma. Several studies have revealed that the cytokine TRAIL (tumor necrosis factor-related apoptosis- inducing ligand) induces apoptosis in a wide variety of tumor cells, but does not cause toxicity to most normal cells. Treating this disease with TRAIL holds great promise, but it is not simple, because the likely agent to treat the disease, recombinant TRAIL, does not last long enough in the body to be effective. We have found a way to have TRAIL reside in another cell such as the natural killer (NK) cell; that cell then secretes TRAIL on a long-term basis. Importantly, NK cells have an additional advantage--they seek out melanoma cells, so they bring TRAIL directly to tumor sites, where it can exert its profound tumor-killing effects. Recent clinical trials have shown that anti-PD-1 (programmed cell death-1) and anti-PD-L1 (programmed cell death-ligand 1) agents have impressive antitumor effects in metastatic melanoma. Thus, we hypothesize that the combination of secretory TRAIL-armed NK cells with anti-PD-1/PD-L1 agents will effectively enhance the tumoricidal efficacy of NK cells. To test the hypothesis, (1) we will assess the biological effect of secretory TRAIL-armed NK cells and anti-PD-1/PD-L1 agents on metastatic melanoma cells, and (2) we will examine the preclinical efficacy of combinatorial immunotherapy with secretory TRAIL-armed NK cells and anti-PD-1/PD-L1 agents in a xenograft mouse model of metastatic melanoma. The proposed studies for the first aim will examine the cytotoxicity of melanoma cells during combined treatment with secretory TRAIL-armed NK cells and anti-PD- 1/PD-L1 agents. In the second aim, we will employ a mouse xenograft model to assess the effect of treatment with secretory TRAIL-armed NK cells in combination with anti-PD-1/PD-L1 agents on growth and regression of metastatic melanoma. We believe that the successful outcome of this study will support the application of this combinatorial immunotherapy to patients with advanced malignant melanoma.

抽象的黑色素瘤是一种严重的皮肤癌，在肤色细胞（黑色素细胞）中形成。当黑色素瘤进展到晚期，治疗选择有限，并且与显着的发病率和死亡。在本次拨款申请中，我们建议开发一种组合免疫疗法来治疗转移性癌症黑色素瘤。多项研究表明，细胞因子 TRAIL（肿瘤坏死因子相关细胞凋亡- 诱导配体）诱导多种肿瘤细胞凋亡，但不会对大多数正常细胞产生毒性细胞。用 TRAIL 治疗这种疾病前景广阔，但并不简单，因为可能的药物治疗这种疾病的重组 TRAIL 在体内持续的时间不够长，无法发挥作用。我们找到了一个让 TRAIL 驻留在另一个细胞（例如自然杀伤 (NK) 细胞）中的方法；然后该细胞在a上分泌TRAIL 长期的基础。重要的是，NK 细胞还有一个额外的优势——它们寻找黑色素瘤细胞，因此它们将TRAIL直接带到肿瘤部位，发挥其深远的肿瘤杀伤作用。最近的临床试验已表明抗 PD-1（程序性细胞死亡-1）和抗 PD-L1（程序性细胞死亡-配体 1）药物对转移性黑色素瘤具有显着的抗肿瘤作用。因此，我们假设组合分泌性 TRAIL 武装 NK 细胞与抗 PD-1/PD-L1 药物的结合将有效增强肿瘤杀伤力 NK细胞的功效。为了检验该假设，（1）我们将评估分泌型 TRAIL 武装的生物学效应 NK 细胞和抗 PD-1/PD-L1 药物对转移性黑色素瘤细胞的作用，以及 (2) 我们将检查临床前分泌型 TRAIL NK 细胞和抗 PD-1/PD-L1 药物联合免疫治疗的疗效转移性黑色素瘤的异种移植小鼠模型。第一个目标的拟议研究将考察分泌型 TRAIL NK 细胞和抗 PD-联合治疗期间黑色素瘤细胞的细胞毒性 1/PD-L1 药物。在第二个目标中，我们将采用小鼠异种移植模型来评估治疗效果分泌性 TRAIL 武装 NK 细胞与抗 PD-1/PD-L1 药物联合使用对生长和消退的影响转移性黑色素瘤。我们相信，本研究的成功结果将支持该技术的应用晚期恶性黑色素瘤患者的联合免疫治疗。