Knuth A, Jäger D, Jäger E
II Medizinische Klinik, Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt am Main, Germany.
Cancer Chemother Pharmacol. 2000;46 Suppl:S46-51. doi: 10.1007/pl00014050.
The identification of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Different groups of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: 1) cancer-testis (CT) antigens, which are expressed in different tumors and normal testis; 2) melanocyte differentiation antigens; 3) point mutations of normal genes; 4) antigens that are overexpressed in malignant tissues; and 5) viral antigens. Clinical studies with peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., delayed-type hypersensitivity (DTH), CTL, autoimmmune, and tumor regression responses. Preliminary results demonstrate that tumor-associated peptides alone elicit specific DTH and CTL responses leading to tumor regression after intradermal injection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was proven effective in enhancing peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Long-lasting complete tumor regressions have been observed after induction of peptide-specific CTLs. However, in single cases with disease progression after an initial tumor response, either a loss of the respective tumor antigen targeted by CTLs or of the presenting major histocompatibility complex (MHC) class I allele was detected as a mechanism of immune escape under immunization. Based on these observations, cytokines to enhance antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1, which is regarded as one of the most immunogenic antigens known today inducing spontaneous immune responses in 50% of patients with NY-ESO-1-expressing cancers. Clinical studies involving antigenic constructs that induce both antibody and CTL responses will show whether these are more effective for immunotherapy of cancer.
免疫系统的细胞或体液效应器所识别的肿瘤相关抗原的鉴定为癌症治疗开辟了新的前景。不同组的癌症相关抗原已被描述为体外和体内细胞毒性T淋巴细胞（CTL）的靶标：1）癌-睾丸（CT）抗原，其在不同肿瘤和正常睾丸中表达；2）黑素细胞分化抗原；3）正常基因的点突变；4）在恶性组织中过表达的抗原；以及5）病毒抗原。已经启动了对源自这些抗原的肽的临床研究，以在体内诱导特异性CTL反应。已经定义了用于评估肽特异性反应的免疫学和临床参数，即迟发型超敏反应（DTH）、CTL、自身免疫和肿瘤消退反应。初步结果表明，单独的肿瘤相关肽在皮内注射后可引发特异性DTH和CTL反应，导致肿瘤消退。粒细胞-巨噬细胞集落刺激因子（GM-CSF）已被证明可通过扩增皮肤肽呈递树突状细胞来有效增强肽特异性免疫反应。在诱导肽特异性CTL后观察到了持久的完全肿瘤消退。然而，在最初的肿瘤反应后疾病进展的个别病例中，检测到CTL靶向的相应肿瘤抗原或呈递的主要组织相容性复合体（MHC）I类等位基因的缺失，作为免疫接种下免疫逃逸的一种机制。基于这些观察结果，正在评估体内增强抗原和MHC I类表达的细胞因子以防止免疫选择。最近，一种利用对肿瘤相关抗原的自发抗体反应（SEREX）的策略导致鉴定出一种新的CT抗原NY-ESO-1，它被认为是当今已知的最具免疫原性的抗原之一，在50%表达NY-ESO-1的癌症患者中诱导自发免疫反应。涉及诱导抗体和CTL反应的抗原构建体的临床研究将表明这些是否对癌症免疫治疗更有效。
