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.

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癌症免疫疗法的治疗功效。治疗性疫苗代表了癌症治疗的一种有吸引力的治疗方式，这主要是由于其特异性和诱导长期持久的免疫记忆的能力，这可能会阻止复发。然而，由于肿瘤进展过程中免疫系统与癌细胞之间发生的相互作用的复杂性质，其治疗潜力仍待部分地实现。这些相互作用主要由两个对立力量调节。靶向肿瘤的免疫机制，用于破坏和肿瘤介导的反机制，使肿瘤能够逃避免疫系统。因此，要成为有效的肿瘤疫苗必须能够产生有效的抗肿瘤免疫反应以及克服治疗作用的免疫回避机制。已经开发了基于TAA的使用的各种癌症疫苗方法在临床前模型中有效。但是，在临床试验环境中，这些疫苗的治疗功效受到限制。尽管其临床效率低下的原因尚不清楚，但缺乏强大的辅助作用，将TAA递送到专业APC和/或存在明显的免疫抑制性免疫逃避机制可能会导致这种影响。为了克服其中一些困难，该应用程序的原则研究者最近开发了一种新型的指定为Protex（TM）的技术。蛋白质（TM）涉及具有修饰形式的核心链霉亲和素形式的嵌合免疫配体，用生物素修饰细胞膜以及用嵌合蛋白进行装饰。这项技术有三个不同的优势。首先，嵌合配体作为四聚体和较高的结构存在，因此有效地将其受体交联免疫细胞以进行有效的信号转导。其次，嵌合蛋白可以单独或在任何生物素化细胞的表面上以快速（<2 hrs）的水平（<2小时），有效（靶向细胞的100％）和耐用（T1/2 =天至周的方式）中的任何生物素化细胞表面显示，而不会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生物素相互作用与生物素化分子共轭，并用作车辆，以将这种分子传递到表达嵌合蛋白的受体的细胞中。该应用程序的原则研究者最近基于使用与生物素化的TAA抗原相结合的4-1BBL嵌合分子，开发了一种新型的，专有的潜在癌症疫苗方法。在初步研究中，这种新型疫苗显示出对免疫系统的先天和适应性臂的有效刺激活性以及对与肿瘤生长有关的T调节细胞的抑制活性。更重要的是，自从该赠款的最后一次提交以来，我们已经证明，用SA-4-1BBL和代表E7的CD8+ T细胞表位的合成肽免疫可以有效地消除宫颈癌动物模型中的已建立肿瘤。因此，该提案的目标是使用B细胞淋巴瘤移植模型来测试和确定Apovax-SVN（TM）疫苗所需的体内条件以及Apovax-SVN（TM）疫苗的治疗效应，以表达Survivin作为TAA的模型。实验性癌症模型中的原理证明确认将为在人类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学疗法和放射治疗的另一种治疗方法，并有望根据真正的癌症分子方法产生更确定的解决方案。 Apoimmune的新型免疫系统疗法Apovax104疫苗是治疗癌症和恶性肿瘤疾病的一种新的创新方法。

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.