GANGLIOSIDE GD2 AS TARGET FOR IMMUNOTHERAPY IN MELANOMA

这项建议的总体目标是应用抗独特型(LD) 基于疫苗的治疗人类黑色素瘤的方法。 二唾液神经节苷脂GD2高密度表达于黑色素瘤细胞和 将被用作免疫治疗的靶点。我们将启动阶段1b 抗id抗体的临床试验，命名为1A7(lgG1-k)，它 在功能上模仿GD2。小鼠抗GD2单抗14G2a 用作免疫抗体或ab1，抗1d1a7(或ab2) 被生成了。1A7用于诱导抗GD2特异性抗体(AB1‘)。 在老鼠、兔子和猴子身上。在这项临床研究中，我们将使用抗LD。 1A7与QS-21佐剂混合主动免疫GD2阳性 黑色素瘤患者。这项试验的目的是1)确定 1A7对患者产生ab3(ab1‘)反应能力的影响 和自体和/或同种异体特异性的细胞溶解T淋巴细胞(CTL) 肿瘤细胞；2)评价1A7的毒性；3)测定 抗1A7抗体的最佳免疫调节剂量；和4)监测 临床反应。在Lb阶段试验结束后，我们将开始 使用最佳免疫调节剂量的II期试验。我们的目标是 也是在动物模型中增强抗GD2免疫反应 基于1A7基因结构的重组DNA疫苗。 这些DNA疫苗将是重组痘苗病毒和重组痘苗病毒的 1A7片段在哺乳动物细胞中的表达。1A7片段将是 一种由重链可变区组成的单链多肽 轻链由15个氨基酸连接物连接。治疗潜力 这些疫苗的评估将通过测定体液和细胞 小鼠的免疫应答及其与标准1A7-QS-21疫苗的比较 还有S的GD2-KLH加QS-21抗原疫苗。所有这些疫苗 将测试肿瘤保护和对已建立的肿瘤的治疗 由EL4细胞组成的免疫活性小鼠淋巴瘤模型 GD2在高密度下。这项研究将是临床试验的前奏。 黑色素瘤患者使用基于第二代抗LD的DNA疫苗。

The overall objective of this proposal is to apply an anti-idiotype(ld) based vaccine approach for the treatment of human melanoma. Disialoganglioside GD2 is expressed at high density on melanoma cells and will be used as a target for immunotherapy. We will initiate a Phase 1b clinical trial with an anti-id antibody, designated 1A7 (lgG1-k), which functionally mimics GD2. Murine monoclonal anti-GD2 antibody 14G2a was used as the immunizing antibody or Ab1, against which anti-ld 1A7 (or Ab2) was generated. 1A7 was used to induce anti-GD2 specific antibodies (Ab1') in mice, rabbits, and monkeys. In this clinical study, we will use anti-ld 1A7 mixed with the QS-21 adjuvant to actively immunize GD2 positive melanoma patients. The objectives of this trial are 1) to determine the effects of 1A7 on the ability of patients to generate Ab3 (Ab1') responses and cytolytic T lymphocytes (CTL) specific for autologous and/or allogeneic tumor cells; 2) to evaluate the toxicity of 1A7; 3) to determine the optimal immunomodulatory dose of the anti-ld 1A7; and 4) to monitor for clinical responses. At the completion of the Phase lb trial, we will begin a Phase II trial using the optimum immunomodulatory dose. Our goal will also be to enhance in animal models the anti-GD2 immune responses by using DNA vaccines based on the structure of 1A7 by recombinant DNA technology. These DNA vaccines will be plasmids and recombinant vaccinia virus capable of expression of 1A7 fragments in mammalian cells. 1A7 fragments will be a single chain polypeptide consisting of the variable domains of the heavy and light chains linked by a 15 amino acid linker. Therapeutic potential of these vaccines will be evaluated by determining the humoral and cellular immune responses in mice and compared with the standard 1A7-QS-21 vaccine as well s the antigen vaccine GD2-KLH plus QS-21. All of these vaccines will be tested for tumor protection and therapy of established tumors in an immunocompetent murine lymphoma model consisting of EL4 cells which express GD2 at high density. This study will be prelude to a clinical trial for melanoma patients with second generation anti-ld based DNA vaccines.