DEVELOPMENT OF CANCER VACCINES

我们已经鉴定了一系列的分化抗原，这些抗原 在人类癌症上表达，在正常组织中表达有限， 已知在癌症宿主中具有潜在的免疫原性。这些 抗原可以分为三个完全不同的类别：小的 整体细胞膜抗原(神经节苷脂，如GM2、GD2和GD3 内酯)、胞内糖蛋白和蛋白质(酪氨酸酶和MAGE-1) 和大的细胞表面粘蛋白，它们也被释放到细胞外 空格(MUC-1、Tf和STN)。针对这些抗原的疫苗将是 在辅助环境中构建、测试和改进，由In指导 体外测定免疫原性。因为地理位置和 这些抗原的化学性质，预期的免疫反应相当 不一样。我们将检测神经节苷脂Tf的血清学反应 和STN抗原，并将遵循血清学，T细胞增殖 对其他抗原的反应和细胞毒性T细胞反应。 增强这些抗原免疫原性的三种基本途径 将用于：与免疫佐剂QS-21混合，接合 到免疫原性载体蛋白，如锁孔帽状血蓝蛋白(KLH)或 在卡介苗等重组载体中表达。一系列循序渐进的 将进行具有疫苗免疫原性的小型临床试验 由血清学和细胞免疫反应定义。在目标1中， 黑色素瘤和肉瘤患者将接种GM2、GD2和 KLH结合疫苗加QS-21的GD3内酯。在目标2中， 诱导抗酪氨酸酶和MAGE-1免疫应答的可行性 将在接种这些蛋白质或疫苗的黑色素瘤患者中进行研究 多肽加上QS-21，或这些蛋白质的KLH结合物或它们的 免疫原性多肽表位。对其氨基酸序列的认识 人类白细胞抗原提呈的酪氨酸酶和MAGE-1表位 抗原可以精确地确定细胞毒性T细胞反应 并且可能会反映出最优的 对其上其他未知多肽的免疫途径 蛋白质。在AIM 3中，MUC-1、Tf和STN-KLH结合物制剂也是如此 作为基因转导的结果表达MUC-1的重组卡介苗， 将被用来诱导免疫反应来对抗这种占优势的乳房 癌症粘蛋白，在没有检测到疾病的乳腺癌患者中 随后在肿瘤标志物升高的乳腺癌患者中也是如此。 每个目标的目标都是优化疫苗并提供 可能成为后续多中心的基础的初步证据 第三阶段试验。

We have identified a series of differentiation antigens which are amply expressed on human cancers, have limited expression on normal tissues and are known to be potentially immunogenic in the cancer bearing host. These antigens can be separated into three quite separate categories: Small integral cell membrane antigens (gangliosides such as GM2, GD2 and GD3 lactone), intracellular glycoproteins and proteins (tyrosinase and MAGE-1) and large cell surface mucins which are also shed into the extracellular space (MUC-1, TF and sTn). Vaccines against these antigens will be constructed, tested and refined in the adjuvant setting, guided by in vitro assays to quantitate immunogenicity. Because of the location and chemical nature of these antigens, the immune responses expected are quite different. We will assay serological responses against ganglioside, TF and sTn antigens, and will follow serologic, T cell proliferative responses and cytotoxic T cell responses against the other antigens. Three basic approaches to augmenting the immunogenicity of these antigens will be used: mixture with the immunological adjuvant QS-21, conjugation to immunogenic carrier proteins such as keyhole limpet hemocyanin (KLH) or expression in recombinant vectors such as BCG. A series of step by step small clinical trials will be conducted with vaccine immunogenicity defined by serological and cell mediated immune responses. In Aim 1, patients with melanoma and sarcoma will be immunized against GM2, GD2 and GD3 lactone by KLH conjugate vaccines plus QS-21. In Aim 2, the feasibility of inducing an immune response against tyrosinase and MAGE-1 will be studied in melanoma patients vaccinated with these proteins or peptides plus QS-21, or KLH conjugates of these proteins or their immunogenic peptide epitopes. Knowledge of the amino acid sequence of peptide epitopes on tyrosinase and MAGE-1 presented by particular HLA antigens permits precise determination of the cytotoxic T cell response against these peptides and will presumably reflect the optimal immunization approach to other not yet identified peptides on these proteins. In Aim 3, MUC-1, TF and sTn-KLH conjugate preparations, as well as recombinant BCG expressing MUC-1 as a consequence of gene transduction, will be used to induce immune responses against this dominant breast cancer mucin, in breast cancer patients who are free of detectable disease and subsequently in breast cancer patients with elevated tumor markers. It is the goal of each Aim to optimize the vaccines and provide preliminary evidence which may be the basis for subsequent multicenter Phase III trials.