Novel APC Vaccine to Induce Anti-Tumor T cell Immunity

说明(申请人提供)：仍然没有几种可靠和简单的疫苗接种方法，在这些方法中，所产生的免疫是可操作的可编程的，仅限于可能具有抗原产生和抗原提呈细胞功能的一种细胞类型，并具有自我放大/自我更新的能力。这种类型的疫苗可能对癌症具有极端的价值。在过去的几年里，这个实验室一直在努力开发这种新的方法。我们发现，在B细胞特异性启动子控制的免疫球蛋白(Ig)基因在B淋巴细胞中靶向表达的体外转基因同基因淋巴细胞一次注射即可免疫成年具有免疫能力的动物。免疫球蛋白基因本身被设计成编码异源表位，以赋予抗原特异性。由于B淋巴细胞是优秀的Ig产生细胞，能高效地将Ig多肽递呈给CD4和CD8T细胞，因此转基因淋巴细胞是一种内源性抗原合成和抗原提呈细胞(APC)功能完美结合的新型细胞疫苗。我们称这个过程为转基因淋巴细胞免疫(TLI)。我们的初步数据表明，这些事件以高保真和高免疫效率发生。TLI只需一次注射70个转基因细胞，就能产生强大的抗原特异性CD4和CTL反应。修订后的申请中提供的新数据还表明，TLI产生针对亚免疫表位的T细胞免疫，随后的免疫在肿瘤保护方面非常有效(&gt；85%)。 提出的工作建立在B淋巴细胞是TLI的关键这一假设的基础上。我们的目标是：(1)阐明TLI诱导抗原特异性CD4和CD8反应的基本机制；(2)将TLI与树突状细胞(DC)接种进行比较；(3)在肿瘤动物模型中测试TLI的保护能力。 目前的疫苗需要提高它们产生免疫类型的能力，这些免疫类型需要(A)增强自然防御或训练免疫系统来开发新的免疫系统，以及(B)保持肿瘤生长动力学和宿主免疫反应之间的平衡，有利于免疫反应。我们认为TLI是一种简单有效的APC疫苗，可以满足这一需求和目标。

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.