Matzku S, Zöller M
Department of Oncology, Biomedical Research, Merck KGaA, Darmstadt, Germany.
Drugs Aging. 2001;18(9):639-64. doi: 10.2165/00002512-200118090-00002.
The concept of immunotherapy of cancer is more than a century old, but only recently have molecularly defined therapeutic approaches been developed. In this review, we focus on the most promising approach, active therapeutic vaccination. The identification of tumour antigens can now be accelerated by methods allowing the amplification of gene products selectively or preferentially transcribed in the tumour. However, determining the potential immunogenicity of such gene products remains a demanding task, since major histocompatibility complex (MHC) restriction of T cells implies that for any newly defined antigen, immunogenicity will have to be defined for any individual MHC haplotype. Tumour-derived peptides eluted from MHC molecules of tumour tissue are also a promising source of antigen. Tumour antigens are mostly of weak immunogenicity, because the vast majority are tumour-associated differentiation antigens already 'seen' by the patient's immune system. Effective therapeutic vaccination will thus require adjuvant support, possibly by new approaches to immunomodulation such as bispecific antibodies or antibody-cytokine fusion proteins. Tumour-specific antigens, which could be a more potent target for immunotherapy, mostly arise by point mutations and have the disadvantage of being not only tumour-specific, but also individual-specific. Therapeutic vaccination will probably focus on defined antigens offered as protein, peptide or nucleic acid. Irrespective of the form in which the antigen is applied, emphasis will be given to the activation of dendritic cells as professional antigen presenters. Dendritic cells may be loaded in vitro with antigen, or, alternatively, initiation of an immune response may be approached in vivo by vaccination with RNA or DNA, given as such or packed into attenuated bacteria. The importance of activation of T helper cells has only recently been taken into account in cancer vaccination. Activation of cytotoxic T cells is facilitated by the provision of T helper cell-derived cytokines. T helper cell-dependent recruitment of elements of non-adaptive defence, such as leucocytes, natural killer cells and monocytes, is of particular importance when the tumour has lost MHC class I expression. Barriers to successful therapeutic vaccination include: (i) the escape mechanisms developed by tumour cells in response to immune attack; (ii) tolerance or anergy of the evoked immune response; (iii) the theoretical possibility of provoking an autoimmune reaction by vaccination against tumour-associated antigens; and (iv) the advanced age of many patients, implying reduced responsiveness of the senescent immune system.
癌症免疫疗法的概念已有一个多世纪的历史，但直到最近才开发出分子层面明确的治疗方法。在本综述中，我们重点关注最具前景的方法——主动治疗性疫苗接种。现在，通过能够选择性或优先扩增在肿瘤中转录的基因产物的方法，可以加速肿瘤抗原的鉴定。然而，确定此类基因产物的潜在免疫原性仍然是一项艰巨的任务，因为T细胞的主要组织相容性复合体（MHC）限制意味着对于任何新定义的抗原，都必须针对任何个体的MHC单倍型确定其免疫原性。从肿瘤组织的MHC分子上洗脱下来的肿瘤衍生肽也是一种很有前景的抗原来源。肿瘤抗原大多免疫原性较弱，因为绝大多数是患者免疫系统已经“见过”的肿瘤相关分化抗原。因此，有效的治疗性疫苗接种将需要佐剂支持，可能需要通过双特异性抗体或抗体 - 细胞因子融合蛋白等免疫调节新方法来实现。肿瘤特异性抗原可能是免疫治疗更有效的靶点，大多由点突变产生，其缺点不仅在于它们是肿瘤特异性的，而且是个体特异性的。治疗性疫苗接种可能会聚焦于以蛋白质、肽或核酸形式提供的特定抗原。无论抗原以何种形式应用，都将重点强调激活作为专职抗原呈递细胞的树突状细胞。树突状细胞可以在体外加载抗原，或者，也可以通过接种RNA或DNA（直接接种或以包装在减毒细菌中的形式接种）在体内引发免疫反应。辅助性T细胞的激活在癌症疫苗接种中直到最近才被考虑在内。细胞毒性T细胞的激活通过提供辅助性T细胞衍生的细胞因子而得到促进。当肿瘤失去MHC I类表达时，辅助性T细胞依赖性募集非适应性防御成分（如白细胞、自然杀伤细胞和单核细胞）尤为重要。成功的治疗性疫苗接种面临的障碍包括：（i）肿瘤细胞针对免疫攻击所形成的逃逸机制；（ii）诱发的免疫反应的耐受性或无反应性；（iii）通过针对肿瘤相关抗原进行疫苗接种引发自身免疫反应的理论可能性；以及（iv）许多患者年龄较大，这意味着衰老的免疫系统反应性降低。
