Tumor antigen-decorated virus-like particles as a therapeutic cancer vaccine

肿瘤抗原修饰的病毒样颗粒作为治疗性癌症疫苗

• 批准号: 8256359
• 负责人: Jaina Patel
• 金额: $ 3.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-30 至 2015-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256359
• 关键词: Adhesions; Affinity Chromatography; Antigen-Presenting Cells; Antigens; Autoimmunity; Breast Cancer Model; CD80 gene; Cancer Vaccine Related Development; Cancer Vaccines; Cancerous; Cell Adhesion Molecules; Cell membrane; Cells; Chinese Hamster Ovary Cell; Clinical; Cytolysis; Development; ERBB2 gene; Effector Cell; Environment; Extracellular Domain; Foundations; Genes; Glycosylphosphatidylinositols; Growth; Human; Immune; Immune response; Immunity; Immunization; Immunosuppression; Immunosuppressive Agents; Incubated; Intercellular adhesion molecule 1; Interleukin-12; Interleukin-2; Knowledge; Lead; Lipid Bilayers; Lipids; Malignant Neoplasms; Membrane; Membrane Glycoproteins; Methods; Modification; Mus; Natural Killer Cells; Nature; Particulate; Peptide Signal Sequences; Prevention; Production; Property; Proteins; Regression Analysis; Regulatory T-Lymphocyte; Site; Standardization; Surface; Technology Transfer; Temperature; Testing; Therapeutic; Time; Toxic effect; Transfection; Treatment Efficacy; Tumor Antigens; Vaccination; Vaccines; Virus-like particle; base; breast cancer vaccine; cancer immunotherapy; cytokine; efficacy testing; immune activation; influenzavirus; malignant breast neoplasm; mast cell; neoplastic cell; novel; outcome forecast; overexpression; receptor; therapeutic vaccine; tool; tumor; uptake; vaccine efficacy

DESCRIPTION (provided by applicant): Cancer immunotherapy provides a promising outlook for the treatment of many cancers. However, tumors have developed strategies to suppress immunity through the formation of immunosuppressive cells, such as regulatory T cells and MDSCs, which can in turn suppress immune effector cells and secrete more immunosuppressive cytokines into the tumor microenvironment. Therefore, the need for a strong therapy to elicit an anti-tumor immune response to overcome any immunosuppressive factors is evident. The particulate natured virus-like particles (VLPs) have been shown to induce a strong immune response, and thus present as a promising tool to overcome immunosuppression by tumors. This proposal studies the incorporation of glycosyl-phosphatidylinositol (GPI)-anchored tumor associated antigens (GPI-TAAs) along with GPI-anchored immunostimulatory molecules (GPI-ISMs), such as cytokines, costimulatory molecules, and adhesion molecules, onto the surface of lipid enveloped VLPs, such as influenza VLPs, by a novel protein transfer approach. The association of TAAs on the surface of VLPs will allow the immune response to be directed against these TAAs that are also associated on tumor cells, whereas the addition of ISMs on the VLP surface along with the TAAs will allow for increased uptake and presentation of the VLPs as well as enhanced activation of antigen presenting cells. Furthermore, inclusion of GPI-cytokines on the surface of VLPs allows for a slow release depot at the immunization site, thus increasing the efficacy of the vaccine. This protein transfer approach requires the use of GPI-anchored proteins to be incubated with enveloped VLPs at 37oC for a short incubation time. Upon incubation, spontaneous incorporation of the GPI-proteins onto the lipid bilayer of the VLPs occurs. This protein transfer method allows us to overcome any cytopathological effects induced when genetically modifying VLPs to express proteins. Thus, this approach also allows for the incorporation of many GPI-proteins onto the same VLP simultaneously and the expression levels of the GPI-proteins can be easily controlled. After production of the resulting chimeric VLPs, we intend to study the efficacy of these protein transferred-VLPs in eliciting tumor regression in mice with established tumors and study the immune correlates that lead to regression by analyzing cellular and humoral immune responses. We will be using a 4T07 murine breast cancer model transfected to express the TAA, HER-2, for these studies. Therefore, we propose to incorporate GPI-HER-2 and GPI-ISMs onto the surface of enveloped VLPs by protein transfer to enhance antitumor immune responses and tumor regression in mice with established tumors. The knowledge obtained from these studies will form a foundation to develop VLP-based efficacious therapeutic cancer vaccines to treat existing tumors or lead to the prevention of metastatic growth in humans. PUBLIC HEALTH RELEVANCE: I propose to enhance antitumor immune responses and induce tumor regression by therapeutically administering enveloped virus-like particles (VLPs) that have been modified to express tumor associated antigens along with immunostimulatory molecules by a protein transfer method. The knowledge obtained from this proposal can lead to the development of effective VLP-based antitumor therapeutic vaccines for human use.

描述（由申请人提供）：癌症免疫疗法为许多癌症的治疗提供了广阔的前景。然而，肿瘤已经发展出抑制免疫的策略，通过形成免疫抑制细胞，如调节性T细胞和MDSCs，这些细胞反过来可以抑制免疫效应细胞，并分泌更多的免疫抑制细胞因子进入肿瘤微环境。因此，需要一个强有力的治疗，以引发抗肿瘤免疫反应，以克服任何免疫抑制因素是显而易见的。颗粒性质的病毒样颗粒（vlp）已被证明可以诱导强烈的免疫反应，因此是克服肿瘤免疫抑制的有希望的工具。本研究通过一种新的蛋白质转移方法，将糖基磷脂酰肌醇（GPI）锚定的肿瘤相关抗原（GPI- taas）与GPI锚定的免疫刺激分子（GPI- isms）（如细胞因子、共刺激分子和粘附分子）结合到脂质包裹的VLPs（如流感VLPs）表面。VLPs表面的TAAs的结合将允许免疫反应直接针对这些与肿瘤细胞相关的TAAs，而在VLP表面添加ISMs和TAAs将允许增加VLPs的摄取和呈递以及增强抗原呈递细胞的激活。此外，在VLPs表面包含gpi -细胞因子允许在免疫部位缓慢释放库，从而提高疫苗的效力。这种蛋白质转移方法需要使用gpi锚定的蛋白质与包裹的VLPs在37℃下孵育，孵育时间短。孵育后，gpi蛋白自发结合到VLPs的脂质双分子层上。这种蛋白质转移方法使我们能够克服基因修饰VLPs表达蛋白质时诱导的任何细胞病理效应。因此，这种方法还允许将许多gpi蛋白同时掺入到同一VLP上，并且gpi蛋白的表达水平可以很容易地控制。在产生嵌合的VLPs后，我们打算研究这些蛋白质转移的VLPs在小鼠肿瘤中诱导肿瘤消退的功效，并通过分析细胞和体液免疫反应来研究导致肿瘤消退的免疫相关因素。在这些研究中，我们将使用转染表达TAA HER-2的4T07小鼠乳腺癌模型。因此，我们建议通过蛋白转移将GPI-HER-2和GPI-ISMs结合到被包膜的VLPs表面，以增强肿瘤小鼠的抗肿瘤免疫反应和肿瘤消退。从这些研究中获得的知识将为开发基于vlp的有效治疗性癌症疫苗奠定基础，以治疗现有肿瘤或预防人类转移性生长。