Ladányi Andrea
Országos Onkológiai Intézet, Tumor Progressziós Osztály, Budapest, Hungary.
Magy Onkol. 2003;47(1):113-7. Epub 2003 Apr 18.
Despite their well-documented immunogenicity, malignant melanomas belong to the most aggressive tumor types. A potential explanation for this is the suboptimal activation of tumor infiltrating T cells. In order to boost immune responses against tumors, a variety of treatment modalities have been tested in animal models and in clinical setting. Antigen-nonspecific approaches (e.g., IFN-alpha and IL-2), as well as active specific immunotherapeutical modalities based on the use of autologous or allogeneic tumor cell-save been investigated in clinical trials of melanoma. The identification of melanoma-associated antigens has opened new avenues in antigen-specific immunotherapy. A promising alternative for the delivery of different forms of melanoma antigens is the application of dendritic cells, the most potent antigen presenting cells capable of eliciting efficient T-cell response. Beside active immunotherapy, immune response against melanoma antigens could be increased through the adoptive transfer of tumor infiltrating lymphocytes or antigen specific T-cell clones. The most important conclusion that can be drawn from the results of published immunotherapy studies is that these modalities are able to induce durable complete tumor regressions,mostly with reasonable toxicity; however, generally only in a minority of patients. This points to the importance of appropriate patient selection, with regard to the expression of the targeted antigens and HLA molecules, as well as to the general immunocompetence of the patients. A crucial and still unsolved question is monitoring immune activation during treatment, although there are promising new tools that could prove useful in this respect. The presence of tumor-reactive CTL in the circulation or in the tumors does not guarantee an efficient immune response. It is important to assess if these T cells are in an activated and functional state. Finally, in several single target antigen-based clinical studies a therapy-induced immunoselection of antigen-negative clones, leading to disease progression, was observed. This could be overcome with the use of antigen cocktails or whole tumor approaches. A better understanding of the mechanisms of action of immunotherapeutical modalities may enhance the success rate of these strategies.
尽管恶性黑色素瘤的免疫原性已有充分记录,但它仍属于最具侵袭性的肿瘤类型之一。对此的一种潜在解释是肿瘤浸润性T细胞的激活不充分。为了增强针对肿瘤的免疫反应,人们在动物模型和临床环境中测试了多种治疗方式。抗原非特异性方法(如干扰素-α和白细胞介素-2),以及基于使用自体或异体肿瘤细胞的主动特异性免疫治疗方式,都已在黑色素瘤的临床试验中得到研究。黑色素瘤相关抗原的鉴定为抗原特异性免疫治疗开辟了新途径。递送不同形式黑色素瘤抗原的一种有前景的替代方法是应用树突状细胞,它是最强大的抗原呈递细胞,能够引发有效的T细胞反应。除了主动免疫治疗外,通过过继转移肿瘤浸润淋巴细胞或抗原特异性T细胞克隆,可以增强针对黑色素瘤抗原的免疫反应。从已发表的免疫治疗研究结果中可以得出的最重要结论是,这些治疗方式能够诱导持久的完全肿瘤消退,且大多具有合理的毒性;然而,通常只有少数患者能够受益。这表明在选择合适的患者时,要考虑靶向抗原和HLA分子的表达,以及患者的总体免疫能力。一个关键且尚未解决的问题是在治疗过程中监测免疫激活,尽管有一些有前景的新工具可能在这方面有用。循环系统或肿瘤中存在肿瘤反应性CTL并不保证有有效的免疫反应。评估这些T细胞是否处于激活和功能状态很重要。最后,在几项基于单一靶抗原的临床研究中,观察到治疗诱导的抗原阴性克隆的免疫选择,导致疾病进展。使用抗原混合物或全肿瘤方法可以克服这一问题。更好地理解免疫治疗方式的作用机制可能会提高这些策略的成功率。