DENDRITIC CELL BASED CANCER VACCINES

表达的粘蛋白分子(MUC-1)糖基化异常 上皮性肿瘤导致新的肿瘤相关核心的暴露 肿瘤特异性抗体识别的蛋白质表位和 细胞毒性T细胞(CTL)。因此，MUC-1粘蛋白可能是 被认为是肿瘤免疫治疗的可能靶点。一位候选人 应用自体树突状细胞的抗粘蛋白细胞疫苗 代替肿瘤细胞呈递肿瘤相关粘蛋白 在黑猩猩身上测试了表位，因为它们表达相同的表位 具有相同序列和组织分布的分子。在……里面 为活体研究做准备，我们从 当时他们正在接受常规体检的各种动物 考试。我们开发了一种培养系统来培育黑猩猩 树突状细胞体外培养(参考文献2)1)。该系统随后在 活着。首先，我们检测了体外培养的DC的迁移潜能。 发现它们恰如其分地迁移到最近的艾宁博士 与T细胞接触并维持其功能的淋巴结节 免疫刺激表型(参考文献2)。然后培养树突状细胞 在体外培养6天，然后加载粘蛋白合成肽 或控制抗原卵清蛋白。负载自体抗原的树突状细胞 然后细胞被静脉注射，动物在体内注射一次抗原 常规佐剂TiterMax。三周后，血液和淋巴 收集并检查节点以用于开发 粘蛋白特异性或卵清蛋白特异性免疫反应。我们发现 树突状细胞在诱导卵清蛋白特异性免疫方面有效，但 不比传统佐剂好多少(参考文献)。3)。我们没有看到 无论哪种方案产生对粘蛋白多肽的免疫力， 证实了我们在体外观察到的这个多肽序列 不包含辅助表位。我们做了另一项研究，使用 相同的MUC1免疫原，但另一种佐剂Leif，已知促进 细胞免疫。我们确实发现了辅助性细胞反应，干扰素-γ 免疫黑猩猩的产生和CTL反应 (参考文献)4)资助NIH/R01 CA57820$166,648 7/01/92-6/30/98 K01 RR00119$56,650 7/01/96-6/30/01出版Barratt-Boyes，S.M. Kao，H.和Finn，O.J.黑猩猩树突状细胞的体外培养 从血单核细胞中提取并用抗原冲击诱导特异性免疫 活体内的反应。J.免疫系统。21：142-148,1998。P51RR00165-38 1/1/1998-12/31/1998耶克斯地区灵长类研究中心

Aberrant glycosylation of the mucin molecule (MUC-1) expressed on epithelial tumors leads to the exposure of novel tumor-associated core protein epitopes which are recognized by tumor specific antibodies and cytotoxic T cells (CTL). Consequently, MUC-1 mucin could be considered a possible target for tumor immunotherapy. A candidate anti-mucin cellular vaccine employing autologous dendritic cells instead of tumor cells for the presentation of tumor associated mucin epitopes was tested in chimpanzees because they express the same molecule with the same sequence and tissue distribution. In preparation for the in vivo studies we obtained blood samples from various animals at the time they were undergoing routine physical examinations. We developed a culture system to grow chimpanzee dendritic cells in vitro (ref. 1). This system was then tested in vivo. First we examined the migration potential of in vitro grown DC and found that they migrate appropriately to the n earest dr aining lymph node where they contact T cells and maintain their immunostimulatory phenotype (ref.2). Dendritic cells were then grown for six days in vitro and then loaded with a mucin synthetic peptide or a control antigen ovalbumin. Autologous antigen loaded dendritic cells were then injected IV, and animals boosted once with antigen in conventional adjuvant TiterMax. Three weeks later blood and lymph nodes were collected and examined for the development of mucin-specific or ovalbumin-specific immune response. We found that dendritic cells were effective at inducing OVA-specific immunity, but not much better that the conventional adjuvant (ref. 3). We saw no immunity generated to the mucin peptide with either regimen, confirming our observations in vitro that this peptide sequence does not contain helper epitopes. We have done another study using the same Muc1 immunogen, but another adjuvant, LeIF, known to promote cellular immunity. We did find helper cell responses, IFN-gamma production and Ctl responses elicited in the immunized chimpanzees (ref. 4) FUNDING NIH/ R01 CA57820 $166,648 7/01/92 - 6/30/98 K01 RR00119 $ 56,650 7/01/96 - 6/30/01 PUBLICATIONS Barratt-Boyes, S.M., Kao, H. and Finn, O.J. Chimpanzee dendritic cells derived in vitro from blood monocytes and pulsed with antigen elicit specific immune responses in vivo. J. Immunother. 21:142-148, 1998. P51RR00165-38 1/1/1998 - 12/31/1998 Yerkes Regional Primate Research Center