Multiple Antigen-Engineered DC Immunication & IFNa Boost for Metastatic Melanoma

项目2：转移性黑色素瘤的多重抗原工程树突状细胞免疫和IFNA Boost 这一应用程序将在我们之前的肿瘤抗原靶向试验中取得进展的基础上，测试新的 以树突状细胞为基础的基因工程疫苗方案旨在更有效地激活CDS和 针对多种黑色素瘤抗原的CD4T细胞。我们将把这项疫苗试验与彻底的 免疫监测以研究T细胞对疫苗的反应和决定因素的重要性 传播以获得临床反应。我们假设接种多种全长肿瘤抗原的疫苗将 激活广泛的CD4和CDS T细胞，以及在进一步激活和 使他们的T细胞反应多样化，以包括他们的肿瘤所表达的其他抗原(或经历“决定因素 将观察客观的临床反应。我们还假设全身性IFNA传递 疫苗接种后会增强疫苗特异性的T细胞反应。 A.具体目标： A.1.使用IFNA Boost进行抗原工程DC试验。我们将用抗原治疗30名受试者 设计DC和随机化一半，以获得IFNA提升。 A2.评估CDS和CD4对免疫抗原MART-1的免疫应答的生物学特性， 酪氨酸酶和MAGE-A6。我们将跟踪CDS和CD4T细胞对这三种免疫抗原的反应， 以及腺病毒载体。我们还将研究TIL对免疫抗原的反应和 肿瘤抗原在可接近的肿瘤沉积中的表达。 A.3.评估行列式扩散。我们还将跟踪CDS和CD4T细胞的反应以明确 黑色素瘤相关抗原不包括在疫苗中，但通常由肿瘤表达(包括 GplOO)和自体肿瘤表达的未知抗原来确定其重要性 决定因素向客观的临床反应扩散。

Project 2: Multiple Antigen-Engineered DC Immunization and IFNa Boost for Metastatic Melanoma This application will build on progress made in our previous tumor antigen targeting trials to test a new genetically engineered dendritic cell-based vaccine regimen designed to more potently activate CDS and CD4 T cells specific to multiple melanoma antigens. We will couple this vaccine trial with thorough immunological monitoring to study T cell responses to the vaccine and the importance of determinant spreading for clinical response. We hypothesize that vaccination with multiple full length tumor antigens will activate a broad range of CD4 and CDS T cells, and that in the subset of patients who further activate and diversify their T cell response to include other antigens expressed by their tumor (or undergo "determinant spreading"), objective clinical response will be observed. We also hypothesize that systemic IFNa delivered after the vaccine will boost the vaccine-specific T cell responses. A. Specific Aims: A.1. Conduct an Antigen-Engineered DC Trial with an IFNa Boost. We will treat 30 subjects with antigen engineered DC and randomize half to receive an IFNa boost. A.2.Assess the Biology of the CDS and CD4 Immune Responses to Immunizing Antigens MART-1, Tyrosinase and MAGE-A6. We will follow CDS and CD4 T cell responses to the three immunizing antigens, as well as the adenovirus vector. We will also investigate TIL responses to the immunizing antigens and tumor antigen expression in accessible tumor deposits. A.3. Assess Determinant Spreading. We will also follow the CDS and CD4 T cell responses to defined melanoma-associated antigens not included in the vaccine but commonly expressed by tumors (including gplOO) and uncharacterized antigens expressed by autologous tumor to determine the importance of determinant spreading to objective clinical response.