Molecular Immunology Group, Cancer Sciences Division, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Cancer Immunol Immunother. 2011 Aug;60(8):1147-51. doi: 10.1007/s00262-011-1042-2. Epub 2011 Jun 5.
Induction of effective immune attack on cancer cells in patients requires conversion of weak tumor antigens into strong immunogens. Our strategy employs genetic technology to create DNA vaccines containing tumor antigen sequences fused to microbial genes. The fused microbial protein engages local CD4+ T cells to provide help for anti-tumor immunity, and to reverse potential regulation. In this review, we focus on induction of CD8+ T cells able to kill target tumor cells. The DNA vaccines incorporate tumor-derived peptide sequences fused to an engineered domain of tetanus toxin. In multiple models, this design induces strong CD8+ T-cell responses, able to suppress tumor growth. For clinical relevance, we have used "humanized" mice expressing HLA-A2, successfully inducing cytolytic T-cell responses against a range of candidate human peptides. To overcome physical restriction in translating to patients, we have used electroporation. Clinical trials of patients with cancer are showing induction of responses, with preliminary indications of suppression of tumor growth and evidence for clinically manageable concomitant autoimmunity.
在患者中诱导对癌细胞的有效免疫攻击需要将弱肿瘤抗原转化为强免疫原。我们的策略利用基因技术创建含有肿瘤抗原序列与微生物基因融合的 DNA 疫苗。融合的微生物蛋白使局部 CD4+T 细胞参与提供抗肿瘤免疫的帮助，并逆转潜在的调节。在这篇综述中，我们重点关注能够杀死靶肿瘤细胞的 CD8+T 细胞的诱导。DNA 疫苗将肿瘤衍生的肽序列与破伤风毒素的工程结构域融合。在多种模型中，这种设计诱导强烈的 CD8+T 细胞反应，能够抑制肿瘤生长。为了临床相关性，我们使用表达 HLA-A2 的“人源化”小鼠，成功地诱导了针对一系列候选人类肽的细胞毒性 T 细胞反应。为了克服转化为患者的物理限制，我们使用了电穿孔。对癌症患者的临床试验显示出诱导反应的迹象，初步表明抑制肿瘤生长，并证明存在可临床管理的伴随自身免疫。
