ANTIIDIOTYPE VACCINE WITH IL2 FOR ADVANCED MELANOMA

申请人的描述（Applicant's Description） 我们已经产生了抗独特型抗体1A 7，这是内部图像 GD 2二唾液酸神经节苷脂 我们在初步试验中证明了 100%的转移性黑色素瘤患者 在充分免疫后，针对GD 2的主动免疫应答 1A 7抗独特型抗体与100 mcg QS-21佐剂混合。 我们 证明了多克隆体液免疫应答，特异性结合 纯化的GD 2二唾液酸神经节苷脂和GD 2阳性细胞，介导 抗体依赖性细胞毒性，主要是IgG 同种型 虽然没有患者对以下药物有客观临床反应， 1A 7，前七名中有三名继续接种疫苗，病情稳定， 14-26个月以上。 毒性仅限于局部反应， 注射，偶尔轻微发烧。 每天皮下注射低剂量IL-2， 毒性极小，可在体内外周血NK细胞扩增数倍 每日剂量范围为0.4至1.5 x 106国际单位/ 平方米的白细胞介素2 为了刺激细胞毒性机制，脉冲剂量的 中等剂量水平IL-2，150万国际单位/米 每两周连续给药三天。 NK细胞 表达Fc受体，并参与抗体依赖性细胞 细胞毒 原则上，能够结合两种肿瘤的抗体 靶细胞和外周血单个核细胞可以递送效应细胞 原发肿瘤部位以及增强细胞毒性。 本研究 建议将联合收割机低剂量IL 2与1A 7抗独特型抗体组合。 这 将进行一项可行性试验， 怀里 这项试验的具体目标是确定最佳免疫 通过1A 7和IL-2的三种方案实现的应答。 额外 研究的具体目的是确定毒性和临床 应答

DESCRIPTION (Applicant's Description) We have generated an anti-idiotype antibody, 1A7, that is the internal image of the GD2 disialoganglioside. We have demonstrated in a preliminary trial that 100 percent of patients with metastatic melanoma will generate an active immune response against GD2 following adequate immunization with the 1A7 anti-idiotype antibody mixed with 100mcg of QS-21 adjuvant. We demonstrated a polyclonal humoral immune response with specific binding to purified GD2 disialoganglioside and GD2 positive cells, that mediated antibody-dependent cellular cytotoxicity, and was predominately of the IgG isotype. While none of the patients had objective clinical responses to 1A7, three of the first seven continue on vaccine with stable disease from 14-26+ months. Toxicity was limited to local reactions at the site of the injection with occasional mild fevers. Low dose daily subcutaneous IL-2 has minimal toxicity and can expand several fold in vivo peripheral blood NK cells in the daily dose range from 0.4 to 1.5 x 106 international units per meter squared of IL-2. To stimulate the cytotoxic mechanism, pulse doses of intermediate dose level IL-2 at 1.5 million international units per meter squared were given for three consecutive days every two weeks. NK cells express Fc receptors and participate in antibody dependent cellular cytotoxicity. In principle, antibodies capable of binding both tumor targets and peripheral blood mononuclear cells could deliver effector cells to primary tumor sites as well as augment cytotoxicity. In this study, we propose to combine low dose IL2 with the 1A7 anti-idiotype antibody. This will be a feasibility trial with ten patients treated on each of the three arms. The specific aims of this trial will be to determine the best immune response achieved by the three schedules of 1A7 and IL-2. Additional specific aims of the study will be to determine toxicities and clinical responses.