Barratt-Boyes S M, Vlad A, Finn O J
Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania 15261, USA. smbb+@pitt.edu
Clin Cancer Res. 1999 Jul;5(7):1918-24.
CTLs and antibody responses to the tumor-associated antigen MUC1 mucin can be detected in patients with adenocarcinomas of the breast, pancreas, colon, and ovary. However, neither response is generally effective at controlling disease. Methods to augment immunity to MUC1 are being designed, with the expectation that this will lead to an antitumor response. The key to eliciting potent immunity to tumor MUC1 may be in generating MUC1-specific T-helper cell responses, which, to date, have not been reported in cancer patients. We have recently demonstrated that a synthetic vaccine representing five copies of the MUC1 tandem repeat peptide can be used to prime MUC1-specific human CD4+ T cells in vitro. Here, we extend these studies to test the immunogenicity and safety of the tandem repeat peptide in the chimpanzee, which has the identical MUC1 tandem repeat sequence to the human. To promote induction of Th1-type responses, we used the novel adjuvant LeIF, a Leishmania-derived protein that is known to stimulate human peripheral blood mononuclear cells (PBMCs) and antigen-presenting cells, to produce a Th1-type cytokine profile. We found that MUC1 tandem repeat peptide administered with LeIF elicited positive, albeit transient, proliferative T-cell responses to MUC1 in the PBMCs from four of four chimpanzees. Immunization induced MUC1-specific IFN-gamma but not interleukin 4 expression in CD4+ T cells from PBMCs and draining lymph nodes. MUC1-specific CTLs were also generated that did not induce detectable autoimmune dysfunction during the 1 year of observation. We conclude that the MUC1 tandem repeat peptide can be used to elicit both T-helper and cytotoxic cell responses to MUC1 in the primate and holds promise as a safe and effective cancer vaccine.
在患有乳腺癌、胰腺癌、结肠癌和卵巢癌的患者中,可以检测到针对肿瘤相关抗原MUC1粘蛋白的细胞毒性T淋巴细胞(CTL)和抗体反应。然而,这两种反应通常都无法有效控制疾病。目前正在设计增强对MUC1免疫的方法,期望这将引发抗肿瘤反应。引发对肿瘤MUC1的有效免疫的关键可能在于产生MUC1特异性辅助性T细胞反应,而迄今为止,癌症患者中尚未有此类报道。我们最近证明,一种代表五个拷贝的MUC1串联重复肽的合成疫苗可用于在体外启动MUC1特异性人类CD4+ T细胞。在此,我们扩展这些研究,以测试串联重复肽在黑猩猩中的免疫原性和安全性,黑猩猩的MUC1串联重复序列与人类相同。为促进Th1型反应的诱导,我们使用了新型佐剂LeIF,一种源自利什曼原虫的蛋白质,已知其可刺激人类外周血单核细胞(PBMC)和抗原呈递细胞,以产生Th1型细胞因子谱。我们发现,与LeIF一起施用的MUC1串联重复肽在四只黑猩猩的PBMC中引发了对MUC1的阳性(尽管是短暂的)增殖性T细胞反应。免疫接种在PBMC和引流淋巴结的CD4+ T细胞中诱导了MUC1特异性干扰素-γ表达,但未诱导白细胞介素4表达。还产生了MUC1特异性CTL,在1年的观察期内未诱导可检测到的自身免疫功能障碍。我们得出结论,MUC1串联重复肽可用于在灵长类动物中引发对MUC1的辅助性T细胞和细胞毒性细胞反应,有望成为一种安全有效的癌症疫苗。