DC VACCINE TO ELICIT POLYSPECIFIC THI ANTI-TUMOR IMMUNIT

描述（由申请人提供）：定义肿瘤抗原的适当来源和 在疫苗中工程化DC以诱导有效的T细胞免疫的策略是现代肿瘤疫苗设计目前面临的两个主要挑战。最近的证据表明，使用肿瘤细胞作为抗原的来源有几个理论上的优势，免疫接种计划的基础上交付的I类限制性表位，和战略，以诱导Th 1型T细胞免疫可能会导致改善客观的临床反应率。在这里，我们建议，通过创新的临床试验和临床前模型，评估和开发改进的治疗性黑色素瘤疫苗，通过利用这些方法。在特异性目的1中，我们将检验以下假设：用同时负载有源自自体黑色素瘤的多种肿瘤抗原的树突状细胞免疫可以诱导有效的抗肿瘤免疫应答。我们将使用自体树突状细胞在转移性黑色素瘤患者中进行3项针对肿瘤的免疫的同时协调I/II期评价。免疫应答的定性和定量疫苗相关变化将与临床结局相关。在特异性目的2中，我们将直接评价和比较抗原 本发明的目的在于研究DC在制备的疫苗中的呈递功能，并且将使用确定的鼠和人体外模型来更精确地解决抗原内化、加工和配体形成的问题。我们的期望是，抗原摄取和呈递的关键特征的比较和阐明将导致开发利用肿瘤细胞作为抗原来源的更有效的抗原递送策略。此外，我们对这些DC疫苗的抗原呈递功能的体外分析可以使我们能够定义临床前测定和DC疫苗的特征，其预测体内免疫原性。SPECIFIC AIM 3的目标是确定有效的方法来增强Th 1型肿瘤反应性CD 4 + T细胞应答，以促进和维持“临床重要的”抗肿瘤免疫。我们将检验这样的假设，即Th 2型抗肿瘤T细胞应答可以被再极化（校正）为IFN-γ相关的Th 1 T细胞应答，并且此后通过含有经调节以产生Th 1偏向性细胞因子的树突细胞的“疫苗”维持为Th 1偏向性应答。总之，这些研究将为设计创新的前瞻性临床前模型和临床疫苗试验奠定基础，从而提高治疗效果和持久的抗肿瘤免疫力。

DESCRIPTION (provided by applicant): Defining an appropriate source of tumor antigen and a strategy for engineering DCs in vaccines to induce efficacious T-cell immunity are two of the major challenges currently facing modem tumor vaccine design. Recent evidence suggests that use of tumor cells as a source of antigen has several theoretical advantages over immunization schemes based on delivery of class I restricted epitopes, and that strategies to induce Th1 type T-cell immunity may result in improved objective clinical response rates. Here we propose, through innovative clinical trials and preclinical models, to evaluate and develop improved therapeutic melanoma vaccines by exploiting these approaches. In SPECIFIC AIM 1 we will test the hypothesis that potent anti-tumor immune responses can be induced by immunization with dendritic cells loaded simultaneously with multiple tumor antigens derived from the autologous melanoma. We will conduct 3 concurrent coordinate phase I/II evaluations of immunization against tumor in patients with metastatic melanoma using autologous dendritic ceils. Qualitative and quantitative vaccine-associated changes in immune responses will be correlated with clinical outcome. In SPECIFIC AIM 2, we will directly evaluate and compare the antigen presentation function of DCs in the vaccines prepared, and will use defined murine and human in vitro models to more precisely address issues of antigen internalization, processing and ligand formation. Our expectation is that the comparison and elucidation of key features of antigen uptake and presentation will lead to the development of more efficient strategies for antigen delivery that utilize tumor cells as a source of antigen. In addition, our in vitro analysis of the antigen presentation function of these DC vaccines may enable us to define preclinical assays, and characteristics of a DC vaccine, which are predictive of in vivo immunogenicity. The goal of SPECIFIC AIM 3 is to determine effective means to enhance Th1-type, tumor-reactive CD4+ T cell responses in order to promote and maintain "clinically-important" anti-tumor immunity. We will test the hypothesis that Th2-type anti-tumor T cell responses can be repolarized (corrected) to IFN- gamma associated Th1 T cell responses and be maintained as Th1-biased responses thereafter by "vaccines" containing dendritic cells conditioned to produce Th1-biasing cytokines. Together, these studies will serve as a foundation for designing innovative prospective preclinical models and clinical vaccine trials allowing for greater therapeutic efficacy and durable anti-tumor immunity.