MELANOMA VACCINE--TYROSINASE/GP100 W/ MONTANIDE ISA51 OR GM CSF

在这个方案中，我们建议扩展在先前的临床试验中所做的观察，在该临床试验中，切除的黑色素瘤患者在接受多肽疫苗免疫后，表现出针对免疫抗原的特异性T细胞免疫增强。在这项试验中，与其他几个用表位多肽免疫黑色素瘤患者的试验一样，使用了不完全弗氏佐剂(IFA)，免疫计划的持续时间很短。癌症疫苗领域有待解决的重要问题包括免疫的最佳剂量、程序和佐剂组合。在目前的试验中，我们将进行一项双中心随机II期试验，在该试验中，切除了IIA和IIB期黑色素瘤的HLA-A2+患者将接种三种疫苗方案中的一种。A组将包括8对酪氨酸酶加IFA和GP 100加IFA的疫苗，作为“标准”疫苗接种的时间间隔越来越长。ARB组的患者将接受与A组相同的一些方案，但使用的是用多肽/IFA组合模拟的封闭共聚佐剂CRL1005。C组的患者将在接种A组相同方案的当天并在接种后四天内在接种部位近端皮下注射GM-CSF。这项研究的主要终点将是对抗原肽的免疫应答和每只手臂上免疫应答的定量比较。这项研究是密歇根大学和南加州大学/诺里斯癌症中心合作进行的。用这些多肽进行皮肤测试，用多肽刺激从外周血中产生的CTL释放细胞因子，以及从ELISPOT试验中估计疫苗接种前后的前体CTL频率将用于衡量免疫反应。还将进行T细胞受体Zeta链表达的评估。这项试验的结果将被用来设计未来在切除高危黑色素瘤患者中进行的随机第三阶段试验的实验臂。在两年的时间里，共对40名患者进行了疫苗接种前后的预处理、皮肤测试和血浆置换，目前正在请求GCRC提供具体的支助。

In this protocol, we propose to extend observations made during a previous clinical trial in which patients with resected melanoma that were immunized with a peptide vaccine demonstrated augmented T cell immunity specifically directed toward the immunizing antigen. In that trial, as in several others in which patients with melanoma were immunized with epitope peptides, incomplete Freund's adjuvant (IFA) was used and the duration of immunization schedules was brief. Important questions that remain to be resolved in the cancer vaccine field include the optimal dose, schedule and adjuvant combination for immunization. In the current trial, we will perform a two center randomized phase II trial in which HLA-A2+ patients with resected stages IIA and IIB melanoma will be vaccinated with one of three vaccine regimens. Arm A will consist of eight paired vaccinations with tyrosinase plus IFA and gp 100 plus IFA over increasing intervals of time as the "standard" regimen. Patients in Arb B will receive the some regimen as in Arm A but with a block co-polymer adjuvant CRL 1005 emusified with the peptide/IFA combination. Patients in Arm C will receive GM-CSF injected subcutaneously proximal to the vaccination site the day of and for four days after vaccination with the same regimen as Arm A. The principal endpoint of the study to be conducted as a collaboration between the University of Michigan andUSC/Norris Cancer Center will be the immu e response to the antigen peptides and a quantitative comparison of immune reaponses on each arm. Skin testing with the peptides, cytokine release by peptide stimulated CTL grown from peripheral blood, and precursor CTL frequency estimated from ELISPOT assays prior to and after vaccinations will be used to measure immune responses. Assessment of T cell receptor zeta chain expression will also be performed. The results of this trial will be used to design the experimental arm of future randomized phase III trials in patients with resected high risk melanoma. Specific GCRC support is being requested for the performance of pretreatment skin testing and plasmapheresis before and after vaccination on a total of 40 patients over two years.