GLYCOLIPID AND PROTEIN VACCINES AGAINST CANCER

我们已经发现分化在人类癌症中大量表达，在癌症患者的正常组织和免疫原性组织中最低限度表达。这些蛋白可分为三大类：小整体细胞膜糖脂（神经节苷GMS2、GD2和GD3）、黑素体糖蛋白（酪氨酸、TRP2、gp75、gp100）和大细胞表面黏液（MUC1）。针对这些抗原的疫苗已经或将在佐剂环境中构建、测试和改进，并在体外定量测定免疫原性的指导下进行。神经节苷类疫苗是最先进的。在所有（GM2）或大多数（GD2和GD3）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类反应。MUC1肽疫苗未能诱导针对肿瘤细胞表面表达的MUC1的高滴度抗体或显著水平的t细胞免疫。光学方法诱导抗体，或辅助或细胞毒性t细胞反应对抗黑素体糖蛋白仍然未经证实。将CTL定义的肽结合到热休克蛋白和以各种方式修饰（异种化）的蛋白质中，是两种在临床前模型中被证明特别有效的方法。我们的具体目标是：1 .在黑色素瘤患者中使用三价KLH结合疫苗（含GM2、GD2和GD3内酯）与单价KLH结合疫苗（含GM2）进行随机佐剂试验。2。确定MUC1肽在每个串联重复诱导剂的1、3或5个位点上的糖基化是否比未糖基化肽在切除乳腺癌患者中的反应更相关。3。将HLA A2限制性酪氨酸酶CTL表位368-377 （370D）和gp100: 209-217 （210M）作为抗原，比较热休克蛋白70 (hsp70) CTL诱导与先前测试的佐剂的诱导效果。IV.比较含有杆状病毒源的人、DNFB半抗原化人或鼠黑素体蛋白（酪氨酸酶、TRP2、gp75、gp100）的疫苗免疫后的抗体、CD4和CD8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.