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

在该方案中，我们建议扩展在先前的临床试验期间所做的观察，在该临床试验中，用肽疫苗免疫的切除黑素瘤患者表现出特异性针对免疫抗原的增强的T细胞免疫。 在该试验中，与用表位肽免疫黑素瘤患者的其他几个试验一样，使用不完全弗氏佐剂（IFA），并且免疫时间表的持续时间很短。 在癌症疫苗领域仍待解决的重要问题包括免疫的最佳剂量、时间表和佐剂组合。 在目前的试验中，我们将进行一项双中心随机II期试验，其中HLA-A2+的IIA和IIB期黑色素瘤切除患者将接种三种疫苗方案之一。 A组将包括8对酪氨酸酶加IFA和gp 100加IFA的配对疫苗接种，时间间隔增加，作为“标准”方案。 ArB B中的患者将接受与A组相同的一些方案，但使用用肽/IFA组合乳化的嵌段共聚物佐剂CRL 1005。 C组的患者将在接种当天和接种后4天接受GM-CSF皮下注射，注射方案与A组相同。密歇根大学和南加州大学/诺里斯癌症中心合作进行的这项研究的主要终点将是对抗原肽的免疫反应以及每只手臂免疫反应的定量比较。肽的皮肤测试、肽刺激的细胞因子释放从外周血中生长的CTL、和前体CTL频率将用于测量免疫应答。 还将评估T细胞受体ζ链表达。 这项试验的结果将用于设计未来在切除高危黑色素瘤患者中进行的随机III期试验的实验组。 正在请求GCRC提供具体支持，以便在两年内对总共40名患者进行疫苗接种前后的预处理皮肤检测和血浆置换。

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.