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: 8526197
• 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/8526197
• 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; tumor microenvironment; 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.

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有前途的前景。然而，肿瘤已经开发出通过形成免疫抑制细胞（例如调节性T细胞和MDSC）来抑制免疫力的策略，这些细胞和MDSC可以又可以抑制免疫效应细胞并分泌更多的免疫抑制细胞因子到肿瘤微环境中。因此，很明显，需要强大的疗法引发抗肿瘤免疫反应以克服任何免疫抑制因素。颗粒天然病毒样颗粒（VLP）已被证明可以诱导强烈的免疫反应，因此作为克服肿瘤免疫抑制的有前途的工具。 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通过一种新型的蛋白质转移方法，脂质包围的VLP，例如流感VLP。 TAA在VLP表面上的关联将允许对这些也与肿瘤细胞相关的TAA进行免疫反应，而在VLP表面上添加ISMS以及TAAS将允许增加摄取和表现。 VLP以及抗原呈递细胞的激活增强。此外，将GPI - 循环动力学纳入VLP的表面，可以在免疫部位释放速度缓慢，从而提高了疫苗的疗效。这种蛋白质转移方法要求将GPI锚定的蛋白在37oC中与包裹的VLP孵育短暂孵育时间。孵育后，发生GPI蛋白自发掺入VLP的脂质双层。这种蛋白质转移方法使我们能够克服遗传修饰VLP表达蛋白质时引起的任何细胞病理效应。因此，这种方法还允许同时将许多GPI蛋白掺入相同的VLP上，并且可以轻松控制GPI-蛋白的表达水平。生产所得的嵌合VLP后，我们打算研究这些蛋白质vlps在具有既定肿瘤的小鼠引发肿瘤消退中的疗效，并研究通过分析细胞和体液免疫反应来导致回归的免疫相关性。对于这些研究，我们将使用转染的4T07鼠乳腺癌模型来表达TAA，HER-2。因此，我们建议通过蛋白质转移将GPI-HER-2和GPIISS纳入包膜VLP的表面，以增强既定肿瘤的小鼠的抗肿瘤免疫反应和肿瘤退化。从这些研究中获得的知识将构成基础，以开发基于VLP的有效治疗癌症疫苗，以治疗现有肿瘤或导致预防人类转移性增长。