PEPTIDE VACCINES WITH/WITHOUT GMCSF IN STAGE IV MELANOMA

唯一的新的全身治疗可切除的高风险和建立 转移性黑色素瘤（IFN α 2B和IL-2） 已经从免疫学方法发展到这种疾病。疫苗 由与黑化相关的谱系抗原组成的黑色素变性是黑色素变性的焦点。 目前的努力是诱导更有效的CD 8 T细胞对黑色素瘤的反应。 酪氨酸酶、gp 100/HMB 45和Melan-A/MART-1分子的表位， 在MHC-I类等位基因HLA-A2的背景下，CD 8 T细胞识别的HLA-A2具有 已经被很好地定义，并被修饰以改善免疫原性，如由 用于ECOG评价的NCI。ECOG/NCI-C III期组间试验E4697测试了 这3种抗原（含Montanide伊萨佐剂）与或不与GM-CSF联合， 可切除晚期的生存期和无进展间期 III期（N+）或IV期（M+）转移性黑色素瘤患者。既不是多表位 肽疫苗，也没有GM-CSF迄今已被研究，如本文所提出的， 没有疾病证据但复发风险很高的患者。的 本申请寻求对CD 8和CD 4 T细胞应答的分析的支持 以及对用于疫苗接种的肽表位的抗体应答。 将从400名HLA-A2+参与者中获得连续血液样本， 通过ELISPOT IFN γ释放测定评价T细胞应答，基于 在肽疫苗试验方面的丰富经验， 匹兹堡CD 4 T细胞反应最近才被确定为谱系 本申请人最近鉴定了一种新的CD 4 在NLA DR 4的背景下识别的Melan-A/MART-1的表位。CD 8应答 该抗原的HLA-A2表位与CD 4应答高度相关。CD4 酪氨酸酶和gp 100的表位已由其他人定义，因此现在 可以测量CD 8和CD 4 T细胞应答以及抗体应答 通过针对黑色素瘤谱系抗原的疫苗接种诱导。该分析 的CD 4和CD 8 T细胞以及B细胞（抗体）的反应， 并将在评估临床疗效时进行 多表位肽疫苗接种和GM-CSF治疗。免疫知识 在这里分析的反应将加快发展的进展， 黑色素瘤疫苗对其他实体瘤的影响。

The only new systemic therapies for resectable high-risk and established metastatic melanoma over the past 30 years (IFN alpha 2B and IL-2) have been developed from immunological approaches to this disease. Vaccines comprised of lineage antigens associated with melanization are the focus of current efforts to induce more effective CD8 T cell responses to melanoma. Epitopes of the tyrosinase, gp100/HMB45, and Melan-A/MART-1 molecules that are recognized by CD8 T cells in the context of the MHC-class I allele HLA-A2 have been well defined, and modified to improve immunogenicity as prepared by the NCI for ECOG evaluation. The ECOG/NCI-C phase III intergroup trial E4697 tests these 3 antigens (with the Montanide ISA adjuvant) with or without GM-CSF in terms of survival and progression-free interval of resectable advanced stage III (N+) or stage IV (M+) metastatic melanoma patients. Neither multi-epitope peptide vaccines, nor GM-CSF have to date been studied as proposed here, in patients without evidence of disease, but at very high risk of relapse. The present application seeks support for analysis of CD8 and CD4 T cell responses as well as antibody responses to the peptide epitopes used for vaccination. Serial blood samples will be obtained from 400 HLA-A2+ participants to be evaluated for T cell responses by ELISPOT IFN gamma release assay, based on an extensive experience in peptide vaccine trials conducted at the University of Pittsburgh. CD4 T cell responses have only recently been identified to lineage antigens of melanoma, and the applicants have recently identified a new CD4 epitope of Melan-A/MART-1 recognized in the context of NLA DR4. CD8 response to the HLA-A2 epitope of this antigen is highly associated with CD4 response. CD4 epitopes of tyrosinase and gp100 have been defined by others, thus it is now possible to measure CD8 and CD4 T cell responses, as well as antibody responses induced by vaccination against the lineage antigens of melanoma. This analysis of CD4 and CD8 T-cell as well as B-cell (antibody) responses is proposed here, and will be performed in relation to assessment of the clinical efficacy of multi-epitope peptide vaccination and GM-CSF therapy. Knowledge of the immune responses to be analyzed here will accelerate progress in the development of vaccines for melanoma on other solid tumors.