DC VACCINE TO ELICIT POLYSPECIFIC THI ANTI-TUMOR IMMUNIT

描述(由申请人提供)：确定适当的肿瘤抗原来源和 在疫苗中设计树突状细胞以诱导有效的T细胞免疫是目前现代肿瘤疫苗设计面临的两大挑战。最近的证据表明，与基于I类限制性表位的免疫方案相比，使用肿瘤细胞作为抗原源有几个理论上的优势，而且诱导Th1型T细胞免疫的策略可能会提高客观的临床应答率。在这里，我们建议通过创新的临床试验和临床前模型，通过利用这些方法来评估和开发改进的治疗性黑色素瘤疫苗。在特定的目标1中，我们将验证这样的假设，即通过同时负载来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反应。我们将对转移性黑色素瘤患者使用自体树突状细胞进行3个同时协调的I/II期肿瘤免疫评估。疫苗相关免疫反应的定性和定量变化将与临床结果相关。在特定的AIM 2中，我们将直接对抗原进行评估和比较 我们还将研究DC在所制备疫苗中的呈递功能，并将使用特定的小鼠和人类体外模型来更准确地解决抗原内化、加工和配体形成的问题。我们的期望是，比较和阐明抗原摄取和呈递的关键特征将导致开发更有效的利用肿瘤细胞作为抗原源的抗原递送策略。此外，我们对这些DC疫苗的抗原提呈功能的体外分析可能使我们能够定义预测体内免疫原性的临床前检测和DC疫苗的特征。特异性AIM 3的目标是确定增强Th1型、肿瘤反应性的CD4+T细胞反应的有效方法，以促进和维持“临床上重要的”抗肿瘤免疫。我们将测试这一假设，即Th2型抗肿瘤T细胞反应可以与干扰素-伽马相关的Th1 T细胞反应重新极化(校正)，并在此后通过含有树突状细胞的疫苗维持为Th1偏向反应，树突状细胞被调节为产生Th1偏向细胞因子。总之，这些研究将作为设计创新的预期临床前模型和临床疫苗试验的基础，从而实现更好的治疗效果和持久的抗肿瘤免疫。

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.