Immune responses to tumour antigens:: implications for antigen specific immunotherapy of cancer
Immune responses to tumour antigens:: implications for antigen specific immunotherapy of cancer
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DOI：
10.1136/jcp.54.9.669
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发表时间：
2001-09-01
影响因子：
3.4
通讯作者：
Knuth, A
中科院分区：
文献类型：
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作者：
Jäger, D;Jäger, E;Knuth, A
由免疫系统的细胞或体液效应器识别的肿瘤相关抗原是抗原特异性癌症免疫治疗的潜在靶点。不同种类的肿瘤抗原在体外和体内都能诱导细胞毒性T淋巴细胞(CTL)反应，即：(1)在不同肿瘤和正常睾丸中表达的“癌睾丸”(CT)抗原，(2)黑素细胞分化抗原，(3)正常基因点突变，(4)在恶性肿瘤组织中过度表达的自身抗原，以及(5)病毒抗原。来自这些抗原的多肽和蛋白的临床研究已经开始，以研究在体内诱导特异性CTL反应的效果。用于评估抗原特异性免疫反应的免疫学和临床参数已被定义为迟发型超敏反应(DTH)、CTL、自身免疫和肿瘤消退反应。在皮内单独给药肿瘤相关多肽后，观察到了特异性的DTH和CTL反应以及肿瘤的消退。用粒细胞巨噬细胞刺激因子(GM-CSF)作为全身佐剂后，可通过增加皮肤抗原提呈郎格汉斯细胞的频率来增强多肽特异性免疫反应。在可测量的多肽特异性CTL的背景下观察到了肿瘤的完全消退。然而，在最初的肿瘤反应后疾病进展的单个病例中，要么检测到CTL靶向的单一抗原丢失，要么检测到呈现主要组织相容性复合体(MHC)I类等位基因，这表明免疫导致了免疫逃逸。在体内调节抗原和MHC-I类表达的细胞因子正在评估中，以防止免疫选择。最近，根据对肿瘤相关抗原的自发抗体反应，发现了一种新的CT抗原NY-ESO-1。NY-ESO-1似乎是迄今已知的最具免疫原性的抗原之一，在50%表达NY-ESO-1的癌症患者中观察到自发免疫反应。临床研究已经开始评估不同结构的NY-ESO-1在体内诱导体液和细胞免疫反应的免疫原性。
Tumour associated antigens recognised by cellular or humoral effectors of the immune system are potential targets for antigen specific cancer immunotherapy. Different categories of cancer antigens have been identified that induce cytotoxic T lymphocyte (CTL) responses in vitro and in vivo, namely: (1) "cancer testis" (CT) antigens, expressed in different tumours and normal testis, (2) melanocyte differentiation antigens, (3) point mutations of normal genes, (4) self antigens that are overexpressed in malignant tissues, and (5) viral antigens. Clinical studies with peptides and proteins derived from these antigens have been initiated to study the efficacy of inducing specific CTL responses in vivo. Immunological and clinical parameters for the assessment of antigen specific immune responses have been defined-delayed type hypersensitivity (DTH), CTL, autoimmmune, and tumour regression responses. Specific DTH and CTL responses and tumour regression have been observed after the intradermal administration of tumour associated peptides alone. Peptide specific immune reactions were enhanced after using granulocyte macrophage stimulating factor (GM-CSF) as a systemic adjuvant by increasing the frequency of dermal antigen presenting Langerhans cells. Complete tumour regression has been observed in the context of measurable peptide specific CTL. However, in single cases with disease progression after an initial tumour response, either a loss of single antigens targeted by CTL or of the presenting major histocompatibility complex (MHC) class I allele was detected, pointing towards immunisation induced immune escape. Cytokines to modulate antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a new CT antigen, NY-ESO-1, has been identified on the basis of spontaneous antibody responses to tumour associated antigens. NY-ESO-1 appears to be one of the most immunogenic antigens known to date, with spontaneous immune responses observed in 50% of patients with NY-ESO-1 expressing cancers. Clinical studies have been initiated to evaluate the immunogenicity of different NY-ESO-1 constructs to induce both humoral and cellular immune responses in vivo.