Zöller Margot, Matzku Siegfried
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Arch Immunol Ther Exp (Warsz). 2002;50(3):197-224.
The concept of immunotherapy of cancer was evoked more than a century ago by W. Coley. Yet it is only recently that the state of knowledge allows for molecularly defined therapeutic approaches and much effort will still be required to place immunotherapy beside of surgery, chemotherapy and radiation as a fourth option. In this review, we will focus chiefly on two aspects: active therapeutic vaccination, because it is our belief that this approach will provide a major breakthrough, and the potential efficacy of combining active vaccination with allogeneic bone marrow cell transplantation. It was recently established in clinical trials that allogeneic bone marrow cell transplantation does not require myeloablative conditioning. Non-myeloabaltive conditioning, which avoids the high toxicity of the conventional approach, it is only kind which allows the recruitment of elderly patients and patients in poor health. Concerning active vaccination protocols, we will address the questions 1) what the targets (i.e. the antigens) of immunotherapeutic approaches could be; 2) how to achieve an optimal confrontation of the immune system with these tumor-associated antigens; and 3) which response elements are needed for raising a therapeutically successful immune reaction against these antigens. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myelablative conditioning to optimize the therapeutic setting for this, most likely, very powerful tool of cancer therapy. We will briefly summarize current considerations to improve engraftment, and reduce graft-versus-host disease while strengthening graft-versus-tumor reactivity. There is some hope that the latter can be "naturally" maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, the efficacy of active vaccination of the allogeneically reconstituted host will provide a pool of virgin T cells which are tolerant towards the host, but not anergized towards tumor antigens presented by MHC molecules of the host. We will only briefly mention supportive regimen of immunomodulation and those hazards which one is most frequently confronted with in attempts to attack tumors with the inherent weapon of immune defense. Though the successful immunotherapy of cancer still remains far behind expectations, there is a solid basis for the belief that, by improving our understanding of the molecular mechanisms of immunity, this may become a very powerful and less harmful tool than conventional therapies.
癌症免疫疗法的概念早在一个多世纪前就由W. 科利提出。然而，直到最近，随着知识水平的提高，才出现了分子层面明确的治疗方法，并且要将免疫疗法作为继手术、化疗和放疗之后的第四种选择，仍需付出巨大努力。在这篇综述中，我们将主要关注两个方面：主动治疗性疫苗接种，因为我们相信这种方法将带来重大突破；以及主动接种与异基因骨髓细胞移植相结合的潜在疗效。最近的临床试验证实，异基因骨髓细胞移植不需要进行清髓预处理。非清髓预处理避免了传统方法的高毒性，是唯一能够招募老年患者和身体状况不佳患者的方法。关于主动疫苗接种方案，我们将探讨以下问题：1）免疫治疗方法的靶点（即抗原）可能是什么；2）如何使免疫系统与这些肿瘤相关抗原实现最佳对抗；3）引发针对这些抗原的治疗性成功免疫反应需要哪些反应元件。在非清髓预处理后的异基因骨髓移植领域，仍有许多问题有待解答，以便优化这种极有可能非常有效的癌症治疗工具的治疗方案。我们将简要总结当前关于改善植入、减少移植物抗宿主病同时增强移植物抗肿瘤反应性的考虑因素。有希望在异基因宿主的T细胞成熟过程中“自然”维持后者。如果这一假设能够得到证实，对异基因重建宿主进行主动接种的疗效将提供一批对宿主耐受但对宿主MHC分子呈递的肿瘤抗原未产生无反应性的初始T细胞。我们将仅简要提及免疫调节的支持性方案以及在用免疫防御的固有武器攻击肿瘤时最常遇到的那些风险。尽管癌症的成功免疫疗法仍远远落后于预期，但有充分的理由相信，通过加深我们对免疫分子机制的理解，免疫疗法可能会成为一种比传统疗法更强大且危害更小的工具。
