Project #4: Investigating the Anti-Tumor Cytotoxicity of Reovirus Treated NK Cells for Cancer Therapy

项目

• 批准号: 9449734
• 负责人: Narendiran Rajasekaran
• 金额: $ 22.06万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9449734
• 关键词: Address; Adoptive Transfer; Alaska Native; Alpha Cell; American Indians; Antibodies; Antitumor Response; Biological Assay; Cancer cell line; Cell Line; Cells; Clinic; Clinical Trials; Colorectal Cancer; Cytokine Activation; Dendritic Cells; Diagnosis; Disease; Double-Stranded RNA; Enzymes; Exhibits; Exposure to; Fc Receptor; Flow Cytometry; Granzyme; Human; Immune response; Immunity; Implant; Incidence; Individual; Infiltration; Injectable; Innate Immune System; Knowledge; Light; Lymphoma; Malignant Neoplasms; Measures; Mediating; Mus; Natural Killer Cells; Nude Mice; Oncolytic viruses; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Play; Population; Pre-Clinical Model; Relapse; Reoviridae; Reovirus; Research; Resistance; Role; Spleen; Surface; Survival Rate; T-Lymphocyte; TNF gene; Testing; Therapeutic; Translating; Treatment outcome; Tumor Cell Line; base; cancer health disparity; cancer therapy; cell killing; colon cancer cell line; cytokine; cytotoxic; cytotoxicity; experimental study; health equity; immunoregulation; improved; in vitro Assay; in vivo; killings; lactate dehydrogenase A; malignant breast neoplasm; mast cell; mortality; neoplastic cell; novel; novel therapeutics; perforin; receptor; response; tumor; tumor progression

PROJECT SUMMARY The survival rate of colorectal cancer and breast cancer as measured by Mortality to incidence ratios (MIRs) is worse among American Indian and Alaskan Native (AI/AN) population as compared to the white population. AI/AN individuals are more likely to be diagnosed with late-stage disease and this leads to poor treatment outcomes and increased mortality. These disparities in cancer within the AI/AN population is compounded by resistance to existing therapies and a high relapse rates among patients. Thus, there is a need to develop novel therapies to cure treatment resistant breast cancer. This study aims to alleviate these disparities faced by the AI/AN population by testing out a new cellular therapeutic approach to treat cancer. NK cells are a key component of the innate immune system and play an important role in early immunity to cancer by killing a variety of tumors. Adoptive transfer of NK cells and NK cell lines is a significant mode of cellular therapy that is being tested in various clinical trials to treat cancers. Efforts are being made to enhance the cytotoxic effects of NK cells and NK cell lines by treating them ex-vivo with different modulating agents. In our recent study, we found that NK cells when treated with reovirus become activated and show an enhanced cytotoxicity against tumor cells. In this project, we will test the ability of reovirus to increase the cytotoxicity of a NK cell line, NK-92MI, against human colorectal cancer cell line-DLD-1. Subsequently, we will perform an adoptive transfer of the reovirus activated NK-92MI cells to treat mice bearing DLD-1 tumors. Results from this study will increase our understanding of NK cell mediated antitumor response and help us develop new strategies to enhance NK cell cytotoxic functions for cancer treatment. Successful completion of this study will provide us with a novel cellular anti-cancer therapy with a potential to be translated into the clinic.

项目摘要 通过死亡率与发病率（MIR）衡量的结直肠癌和乳腺癌的存活率为 与白人人口相比，美洲印第安人和阿拉斯加本地人（AI/AN）人口更糟糕。 AI/一个人更有可能被诊断出患有晚期疾病，这导致治疗不佳 结果和死亡率增加。 AI/AN人群中癌症的这些差异是由 对现有疗法的抵抗力和患者的高复发率。因此，有必要发展小说 治疗耐药性乳腺癌的疗法。这项研究旨在减轻 通过测试一种新的细胞治疗方法来治疗癌症，AI/一个人群。 NK单元是关键组成部分 固有的免疫系统和通过杀死各种肿瘤的早期免疫力在癌症中发挥重要作用。 NK细胞和NK细胞系的过继转移是一种重要的细胞治疗方式，正在测试中 各种临床试验以治疗癌症。正在努力增强NK细胞的细胞毒性作用和 NK细胞系通过使用不同的调节剂治疗外部的细胞系。在我们最近的研究中，我们发现NK 细胞用葡萄病毒治疗被激活并显示出对肿瘤细胞的细胞毒性增强。在这个 项目，我们将测试异病毒增加NK细胞系NK-92MI的细胞毒性的能力，对人类 结直肠癌细胞系列-DLD-1。随后，我们将对激活的葡萄病毒进行收养转移 NK-92MI细胞以治疗带有DLD-1肿瘤的小鼠。这项研究的结果将增加我们对NK的理解 细胞介导的抗肿瘤反应，并帮助我们制定新的策略，以增强NK细胞细胞毒性功能 癌症治疗。这项研究的成功完成将为我们提供一种新型的细胞抗癌治疗 有可能翻译成诊所。