GLYCOLIPID AND PROTEIN VACCINES AGAINST CANCER

我们已经鉴定了在人类癌症上大量表达的分化，在正常组织上最低限度表达，并且在癌症患者中具有免疫原性。这些分为三大类：小完整细胞膜糖脂（神经节苷脂GMS 2，GD 2和GD 3），黑素体糖蛋白（酪氨酸，TRP 2，gp 75，gp 100）和大细胞表面粘蛋白（MUC 1）。针对这些抗原的疫苗已经或将要在佐剂环境中构建、测试和改进，通过体外测定来定量免疫原性。本项目前期完善的神经节苷脂疫苗是最先进的。在所有（GM 2）或大多数（GD 2和GD 3）病例中，这些疫苗诱导的抗体与肿瘤细胞上表达的相同神经节苷脂反应。MUC 1肽疫苗未能诱导针对肿瘤细胞表面表达的MUC 1的高滴度抗体或显著水平的T细胞免疫。诱导针对黑素体糖蛋白的抗体或辅助性或细胞毒性T细胞反应的光学方法尚未得到证实。使用CTL限定的肽掺入热休克蛋白和以各种方式修饰（异种化）的蛋白是两种在临床前模型中已被证明特别有效的方法。我们的具体目标是：在黑色素瘤患者中进行一项使用三价KLH结合疫苗（含GM 2、GD 2和GD 3内酯）与单价KLH结合疫苗（含GM 2）的随机辅助试验。二.确定在切除的乳腺癌患者中，每个串联重复序列在1、3或5个位点糖基化的MUC 1肽是否比未糖基化的肽诱导更相关的反应。三.以酪氨酸酶368-377（370 D）和gp 100：209-217（210 M）的HLA A2限制性CTL表位为抗原，比较热休克蛋白70（hsp 70）与先前测试的佐剂的CTL诱导。四.比较用含有杆状病毒来源的人、DNFB半抗原化的人或鼠黑素体蛋白（酪氨酸酶、TRP 2、gp 75、gp 100）的疫苗免疫后的抗体、CD 4和CD 8应答。

We have identified differentiation abundantly expressed on human cancers, minimally expressed on normal, tissues and immunogenic in cancer patients. These divide into three broad groups: small integral cell membra vgvvne glycolipids (gangliosides GMS2, GD2 and GD3), melanosomal glycoproteins (tyrosine, TRP2, gp75, gp100) and large cell surface mucines (MUC1). Vaccines against these antigens have been or will be constructed, tested and refined in the adjuvant setting, guided by in vitro assays to quantitate immunogenicity. Ganglioside vaccines perfected previously under this Program Project are most advanced. Antibodies induced by these vaccines react with the same gangliosides expressed on tumor cells in all (GM2) or most (GD2 and GD3) cases. MUC1 peptide vaccines have failed to induce high titers of antibodies or significant levels of T-cell immunity against MUC1 expressed at the tumor cell surface. The optical approach for inducing antibody, or helper or cytotoxic T-cell responses against the melanosomal glycoproteins remains unproven. The use of CTL defined peptides incorporated into heat shock proteins and proteins modified (xenogenized) in various ways are two approaches that have proven particular potent in preclinical models. Our specific aims are: I. Conduct a randomized adjuvant trial in melanoma patients using a trivalent KLH conjugate vaccine (containing GM2, GD2 and GD3 lactone) versus a monovalent KLH conjugate vaccine (containing GM2). II. Determine whether MUC1 peptide glycosylated at 1, 3, or 5 sites per tandem repeat inducers a more relevant response than the unglycosylated peptide in patients with resected breast cancer. III. Compare the CTL induction of heat shock protein 70 (hsp70) with that of previously tested adjuvants using the HLA A2 restricted CTL epitopes of tyrosinase: 368-377 (370D) and gp100: 209-217 (210M) as antigens. IV. Compare antibody, CD4 and CD8 responses after immunization with vaccines containing human, DNFB haptenized human or murine melanosomal proteins (tyrosinase, TRP2, gp75, gp100) of baculovirus origin.