Novel APC Vaccine to Induce Anti-Tumor T cell Immunity

诱导抗肿瘤 T 细胞免疫的新型 APC 疫苗

• 批准号: 6607004
• 负责人: MAURIZIO ZANETTI
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607004
• 关键词: B lymphocyte; T lymphocyte; antigen presenting cell; biotechnology; cellular immunity; cytotoxic T lymphocyte; dendritic cells; helper T lymphocyte; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer vaccine; transfection; tumor antigens; vaccine development; vector vaccine

DESCRIPTION (provided by the applicant): There are still few reliable and simple methods of vaccination in which the resulting immunity is operationally programmable, restricted to possibly one cell type functioning as antigen producing and antigen presenting cell, and endowed with self-amplifying/self-renewing capacity. This type of vaccine could be of extreme value against cancer.For the past years this laboratory has worked towards developing such a new approach. We established that an adult immunocompetent animal can readily be immunized with a single injection of syngeneic lymphocytes made transgenic in vitro for immunoglobulin (Ig) genes controlled by a B cell specific promoter for targeted expression in B lymphocytes. The Ig genes are themselves engineered to code for heterologous epitopes to confer antigen specificity. Since B lymphocytes are excellent Ig producers and present Ig peptides to CD4 and CD8 T cells very efficiently, transgenic lymphocytes are a novel form of cell vaccine in which endogenous synthesis of antigen and antigen presenting cell (APC) function are ideally combined. We term this process Transgenic Lymphocyte Immunization (TLI). Our preliminary data indicate that these events occur with high fidelity and at high immunological efficiency. TLI lends itself to a robust antigen-specific CD4 and CTL responses with a single injection of as few as 70 transgenic cells. New data provided in the revised application also demonstrate that TLI generates T cell immunity against sub-immungenic epitopes and that the ensuing immunity is highly effective (>85 percent) in tumor protection. The work proposed is built on the hypothesis that B lymphocytes are key to TLI. It is our goal to: (1) elucidate the basic mechanisms of TLI for the induction of antigen-specific CD4 and CD8 responses; (2) compare TLI to vaccination with dendritic cells (DC); and (3) test TLI ability to protect in animal models of tumor. Current vaccines need to be improved with respect to their ability to generate the type of immunity needed to (a) enhance natural defenses or train the immune system to develop new ones, and (b) keep the balance between the tumor growth kinetics and the host immune response in favor of the immune response. We believe that TLI is a simple and effective form of APC vaccine that can meet this need and objectives.

描述（由申请人提供）：仍然很少有可靠且简单的疫苗接种方法，其中所产生的免疫力在操作上是可编程的，仅限于一种细胞类型，可作为抗原产生和抗原呈现细胞，并具有自我扩增/自我更新能力。这种类型的疫苗可能对癌症具有极大的价值。在过去的几年中，该实验室致力于开发这种新方法。我们确定，成年免疫能力动物可以轻松地通过单次注射合成性淋巴细胞进行免疫，从而在体外进行转基因，用于由B细胞特异性启动子控制的免疫球蛋白（IG）基因（IG）基因，用于B淋巴细胞中靶向表达。 IG基因本身是为异源表位的代码设计的，以赋予抗原特异性。由于B淋巴细胞是极好的Ig生产剂，并且非常有效地呈现给CD4和CD8 T细胞的Ig肽，因此转基因淋巴细胞是一种新型的细胞疫苗形式，其中抗原和抗原出现细胞（APC）功能的内源性合成是理想的组合。 我们称这种过程转基因淋巴细胞免疫（TLI）。 我们的初步数据表明，这些事件以高忠诚和高免疫学效率发生。 TLI将自己适合于稳健的抗原特异性CD4和CTL反应，单一注射少于70个转基因细胞。修订后的应用程序中提供的新数据还表明，TLI对亚不符号表位产生T细胞免疫力，并且随后的免疫力在肿瘤保护方面非常有效（> 85％）。 提出的工作建立在B淋巴细胞是TLI的关键的假设上。我们的目标是：（1）阐明TLI诱导抗原特异性CD4和CD8响应的基本机制； （2）将TLI与树突状细胞（DC）进行比较； （3）测试TLI在肿瘤动物模型中保护的能力。 当前的疫苗需要改善其产生（a）增强自然防御或训练免疫系统所需免疫力类型的能力，以及（b）保持肿瘤生长动力学和免疫反应之间的平衡，以支持免疫反应。 我们认为TLI是一种简单有效的APC疫苗，可以满足这种需求和目标。