PEPTIDE VACCINES WITH/WITHOUT GMCSF IN STAGE IV MELANOMA

唯一可切除的高危和已确定的系统治疗方法 过去30年转移性黑色素瘤(干扰素α2B和IL-2) 都是从免疫学方法发展而来的。疫苗 由与黑化相关的谱系抗原组成的是 目前正在努力诱导更有效的CD8 T细胞对黑色素瘤的反应。 酪氨酸酶、gp100/HMB45和Melan-A/Mart-1分子的表位 由CD8 T细胞识别的MHC-I类等位基因HLA-A2有 定义良好，并进行修改以提高免疫原性，如 用于ECOG评估的NCI。ECOG/NCI-C第三阶段组间试验E4697试验 这3个抗原(与Montanide ISA佐剂一起)在有或没有GM-CSF的情况下 可切除晚期患者的生存条件和无进展间期 III期(N+)或IV期(M+)转移性黑色素瘤患者。既不是多表位 到目前为止，还没有像这里建议的那样研究多肽疫苗，也没有研究GM-CSF，在 没有疾病证据，但复发风险很高的患者。这个 本申请寻求对CD8和CD4T细胞反应分析的支持 以及对用于疫苗接种的多肽表位的抗体反应。 将从400名人类白细胞抗原A2+参与者中采集连续血液样本 通过ELISPOT干扰素γ释放试验评估T细胞反应，基于 在加州大学进行的多肽疫苗试验方面有丰富的经验 匹兹堡。直到最近才发现CD4T细胞对谱系的反应 黑色素瘤的抗原，申请人最近发现了一种新的CD4 在NLA DR4的背景下识别的Melan-A/Mart-1的表位。CD8对 该抗原的HLA-A2表位与CD4应答密切相关。CD_4 酪氨酸酶和gp100的表位已经被别人定义了，所以现在是这样。 可以测量CD8和CD4T细胞反应以及抗体反应 通过接种黑色素瘤的谱系抗原而诱导的。这一分析 在这里提出了CD4和CD8 T细胞以及B细胞(抗体)的反应， 并将在评估其临床疗效时进行 多表位多肽疫苗和GM-CSF治疗。关于免疫的知识 将在这里分析的答复将加快发展 其他实体肿瘤上的黑色素瘤疫苗。

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.