ApoVax-SVN as a Novel Vaccine for Cancer Immunotherapy

ApoVax-SVN 作为癌症免疫治疗的新型疫苗

基本信息

批准号：
7326239
负责人：
Haval Shirwan
金额：
$ 32.83万
依托单位：
APOVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-06 至 2009-03-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7326239
关键词：
Activated Lymphocyte Acute Adjuvant Adverse effects Animal Model Animals Antibody Formation Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Applications Grants B-Cell Lymphomas Binding Biotin CD8B1 gene Cancer Model Cancer Patient Cancer Vaccines Cause of Death Cell Differentiation process Cell membrane Cells Chimeric Proteins Clinical Clinical Trials Complex Condition Dendritic Cells Dendritic cell activation Developed Countries Developing Countries Development Disease Dose Effectiveness Enzyme-Linked Immunosorbent Assay Extracellular Domain Figs - dietary Generations Goals Grant Human Immune Immune Targeting Immune response Immune system Immunization Immunologic Memory Immunotherapy In Vitro Inbred BALB C Mice Injection of therapeutic agent Life Ligands Lymphocyte antigen Maintenance Major Histocompatibility Complex Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Marketing Mediating Modality Modeling Modification Molecular Mus Natural Killer Cells Nature Operative Surgical Procedures Patients Peptides Phase Phase I Clinical Trials Play Pre-Clinical Model Prevention Protein Isoforms Radiation Radiation therapy Recurrence Research Personnel Role Series Signal Transduction Small Business Technology Transfer Research Solutions Specificity Staining method Stains Streptavidin Structure Surface Survivin Antigen T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Protocols Tumor Antigens United States Upper arm Vaccinated Vaccines Week Work base cancer cell cancer immunotherapy cancer prevention cancer therapy cell mediated immune response chemotherapy concept crosslink cytokine day design desire in vivo innovation interest macrophage mouse model neoplastic new technology novel novel vaccines prevent prophylactic protein function receptor response size success survivin synthetic peptide therapeutic effectiveness therapeutic vaccine tumor tumor growth tumor progression vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): The main objective of this proposal is to develop a novel cancer vaccine, ApoVax-SVN(tm) based on the use of a proprietary costimulatory chimeric ligand, 4-1BBL, designed to specifically deliver survivin, a tumor associated antigen (TAA) to professional antigen-presenting cells (APCs) and activate them for the generation of an effective anti-tumor immune response with therapeutic efficacy for cancer immunotherapy. Therapeutic vaccines represent an attractive treatment modality for the management of cancer, primarily due to their specificity and ability to induce long lasting immunological memory that may prevent against recurrences. However, their therapeutic potential remains to be realized partially due to the complex nature of interactions taking place between the immune system and cancer cells in the course of tumor progression. These interactions are primarily regulated by two opposing forces; immune mechanisms that target the tumor for destruction and tumor-mediated counter-mechanisms that enable the tumor to evade the immune system. As such, to be effective tumor vaccines must be capable of generating a potent anti-tumor immune response as well as overcoming immune evasive mechanisms for a therapeutic effect. Various cancer vaccine approaches based on the use of TAAs have been developed and shown effective in preclinical models. However, the therapeutic efficacy of these vaccines has been limited in clinical trial settings. Although the reasons for their clinical inefficacy remain unknown, the lack of a strong adjuvant effect, ineffective delivery of TAAs to professional APCs, and/or the presence of significant immunoinhibitory immune evasion mechanisms may contribute to this effect. To overcome some of these difficulties, a novel technology designated as ProtEx(tm) has recently been developed by the Principle Investigator of this application. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin, modification of the cell membrane with biotin, and decoration with chimeric proteins. There are three distinct advantages to this technology. First, chimeric ligands exist as tetramers and higher structures, and as such effectively crosslink their receptors on immune cells for potent signal transduction. Second, chimeric proteins can be displayed singly or in a combination on the surface of any biotinylated cell at desired levels in a rapid (< 2 hrs), efficient (100% of the targeted cells), and durable (t1/2= days to weeks) manner without compromising the function of the protein or the cell. Third, chimeric proteins can be conjugated to biotinylated molecules of interest via streptavidin/biotin interaction and used as vehicles to deliver such molecules to cells of interest expressing receptors for the chimeric proteins. The Principle Investigator of this application recently developed a novel, proprietary potential cancer vaccine approach based on the use of 4-1BBL chimeric molecule conjugated to biotinylated TAA antigens. In preliminary studies, this novel vaccine showed potent stimulatory activity on the innate as well as adaptive arms of the immune system and inhibitory activity on T regulatory cells implicated in tumor growth. More importantly, since the last submission of this grant we have demonstrated that immunization with SA-4-1BBL plus a synthetic peptide representing the CD8+ T cell epitope of E7 was effective in eradicating established tumors in a cervical cancer animal model. Therefore, the objectives of this proposal are to test and determine in vivo conditions required for protective as well as therapeutic effects of ApoVax-SVN(tm) vaccine using a B cell lymphoma transplantable model expressing survivin as a TAA. Proof-of-principle confirmation in experimental cancer models will pave the way for testing this novel concept in human clinical trials. Immune system-based treatment of cancer represents an alternative therapeutic approach to classic chemotherapy and radiation treatment, and promises to yield a more definitive solution based on a true molecular approach to cancer. ApoImmune's novel immune system-based therapy, ApoVax104 vaccine, is a new, innovative approach to treating cancer and malignant neoplastic diseases.

描述（由申请人提供）：该提案的主要目标是开发一种新型癌症疫苗 ApoVax-SVN(tm)，该疫苗基于使用专有的共刺激嵌合配体 4-1BBL，旨在特异性递送生存素（一种肿瘤）相关抗原（TAA）与专业抗原呈递细胞（APC）结合，并激活它们以产生有效的抗肿瘤免疫反应，从而对癌症免疫治疗产生疗效。治疗性疫苗代表了一种有吸引力的癌症治疗方式，主要是因为它们的特异性和诱导持久免疫记忆的能力，可以防止复发。然而，由于肿瘤进展过程中免疫系统和癌细胞之间相互作用的复杂性，它们的治疗潜力仍有待实现。这些相互作用主要由两种相反的力量调节；针对肿瘤进行破坏的免疫机制以及使肿瘤能够逃避免疫系统的肿瘤介导的反机制。因此，有效的肿瘤疫苗必须能够产生有效的抗肿瘤免疫反应，并克服免疫逃避机制以达到治疗效果。基于 TAA 的各种癌症疫苗方法已经被开发出来，并在临床前模型中显示出有效的效果。然而，这些疫苗的治疗效果在临床试验中受到限制。尽管其临床无效的原因仍不清楚，但缺乏强佐剂作用、TAA 向专业 APC 的无效递送和/或存在显着的免疫抑制性免疫逃避机制可能导致这种效应。为了克服其中一些困难，该应用的原理研究员最近开发了一种名为 ProtEx(tm) 的新技术。 ProtEx(tm) 涉及生成具有修饰形式的核心链霉亲和素的嵌合免疫配体、用生物素修饰细胞膜以及用嵌合蛋白修饰。这项技术具有三个明显的优势。首先，嵌合配体以四聚体和更高结构存在，因此有效地交联免疫细胞上的受体以进行有效的信号转导。其次，嵌合蛋白可以快速（< 2小时）、高效（100%的目标细胞）和持久（t1/2=天数）以所需水平单独或组合地展示在任何生物素化细胞的表面上。周）的方式，而不损害蛋白质或细胞的功能。第三，嵌合蛋白可以通过链霉亲和素/生物素相互作用与生物素化的目标分子缀合，并用作载体将此类分子递送至表达嵌合蛋白受体的目标细胞。该应用的主要研究者最近开发了一种新颖的、专有的潜在癌症疫苗方法，该方法基于使用与生物素化 TAA 抗原缀合的 4-1BBL 嵌合分子。在初步研究中，这种新型疫苗对免疫系统的先天性和适应性臂显示出强大的刺激活性，并对与肿瘤生长有关的 T 调节细胞具有抑制活性。更重要的是，自上次提交这项资助以来，我们已经证明，用 SA-4-1BBL 加上代表 E7 的 CD8+ T 细胞表位的合成肽进行免疫，可有效根除宫颈癌动物模型中已形成的肿瘤。因此，本提案的目的是使用表达生存素作为 TAA 的 B 细胞淋巴瘤可移植模型来测试和确定 ApoVax-SVN(tm) 疫苗的保护和治疗效果所需的体内条件。实验癌症模型中的原理验证确认将为在人体临床试验中测试这一新概念铺平道路。基于免疫系统的癌症治疗代表了经典化疗和放射治疗的替代治疗方法，并有望在真正的癌症分子方法的基础上产生更明确的解决方案。 ApoImmune 的新型基于免疫系统的疗法 ApoVax104 疫苗是一种治疗癌症和恶性肿瘤疾病的创新方法。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

DOI：
10.1371/journal.pone.0042459
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Madireddi S;Schabowsky RH;Srivastava AK;Sharma RK;Yolcu ES;Shirwan H
通讯作者：
Shirwan H

SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.

DOI：
10.1016/j.vaccine.2010.06.073
发表时间：
2010-08-16
期刊：
VACCINE
影响因子：
5.5
作者：
Sharma, Rajesh K.;Srivastava, Abhishek K.;Yolcu, Esma S.;MacLeod, Kathryn J.;Schabowsky, Rich-Henry;Madireddi, Shravan;Shirwan, Haval
通讯作者：
Shirwan, Haval

SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.