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

项目2：多抗原工程化DC免疫和IFNa加强治疗转移性黑色素瘤 这项应用将建立在我们以前的肿瘤抗原靶向试验的基础上，以测试一种新的 基于基因工程树突状细胞的疫苗方案，旨在更有效地激活CDS， 对多种黑色素瘤抗原特异的CD 4 T细胞。我们将把这次疫苗试验与彻底的 免疫监测研究T细胞对疫苗的反应和决定因素的重要性 传播临床反应。我们假设用多种全长肿瘤抗原进行疫苗接种， 激活广泛的CD 4和CD 8 T细胞，并且在进一步激活和 使他们的T细胞应答多样化以包括由他们的肿瘤表达的其他抗原（或经历“决定簇”免疫应答）。 扩散”），将观察客观临床反应。我们还假设系统性IFNa递送 疫苗接种后会增强疫苗特异性T细胞的反应。 A.具体目标： A.1.使用IFNa加强进行抗原工程化DC试验。我们将用抗原治疗30名受试者 工程DC和随机化一半接受IFNa增强。 A.2.评估CDS和CD 4对免疫抗原MART-1的免疫应答的生物学， 酪氨酸酶和MAGE-A6。我们将跟踪CDS和CD 4 T细胞对三种免疫抗原的应答， 以及腺病毒载体。我们还将研究TIL对免疫抗原的应答， 肿瘤抗原在可及肿瘤沉积物中的表达。 A.3.评估决定性传播。我们还将跟踪CDS和CD 4 T细胞反应，以确定 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 gp 100）和自体肿瘤表达的未表征抗原，以确定 决定因素扩散到客观临床应答。

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.