GLYCOLIPID AND PROTEIN VACCINES AGAINST CANCER

我们已经鉴定了分化在人类癌症中大量表达，在正常组织中表达最低，在癌症患者中表达免疫原性。它们分为三大类：小细胞膜vgvvne糖脂(神经节苷脂GMS2、GD2和GD3)、黑素体糖蛋白(酪氨酸、Trp2、gp75、gp100)和大细胞表面粘蛋白(MUC1)。针对这些抗原的疫苗已经或将在佐剂环境中构建、测试和提纯，并在体外试验的指导下定量测定免疫原性。以前在本计划项目下完善的神经节苷脂疫苗是最先进的。在ALL(GM2)或大多数(GD2和GD3)病例中，由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。MUC1多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。诱导抗体、辅助性或细胞毒性T细胞对黑素体糖蛋白的反应的光学方法仍未得到证实。使用CTL定义的多肽结合到热休克蛋白和以不同方式修饰(异种)的蛋白是两种已被证明在临床前模型中特别有效的方法。我们的具体目标是：1.在黑色素瘤患者中进行一项随机辅助试验，分别使用三价KLH结合疫苗(包含GM2、GD2和GD3内酯)和单价KLH结合疫苗(包含GM2)。II.在乳腺癌切除患者中，确定在每个串联重复序列的1、3或5位点处糖基化的MUC1多肽是否比未糖基化的多肽诱导更相关的反应。III.以HLAA2限制的酪氨酸酶CTL表位368-377(370D)和gp100：209-217(210M)为抗原，比较热休克蛋白70(HSP70)和先前试验佐剂的CTL诱导作用。IV.比较含有人、DNFB半致敏的人或鼠的杆状病毒来源的黑素体蛋白(酪氨酸酶、Trp2、gp75、gp100)的疫苗免疫后的抗体、CD4和CD8反应。

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.