Ko Eric C, Wang Xinhui, Ferrone Soldano
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Int Arch Allergy Immunol. 2003 Dec;132(4):294-309. doi: 10.1159/000074897.
In recent years, there has been growing interest in the application of immunotherapy as an alternative to chemotherapy and radiotherapy for the treatment of malignant diseases. This interest is due to a variety of factors, including revival of the immunosurveillance theory, availability of well-defined and structurally characterized human tumor-associated antigens (TAAs), progress in our understanding of the molecular pathways required for induction and maintenance of an immune response, and advances in methodologies to generate TAA-specific cytotoxic T lymphocytes (CTLs) and monoclonal antibodies (mAbs) as immunological probes. However, contrary to the positive results obtained with TAA-specific immunotherapy in animal model systems, the clinical response in patients has been disappointing. Frequently, the immune responses do not correlate with the clinical responses. Analysis of the underlying mechanisms of this dichotomy have identified the low immunogenicity of TAAs, the lack of immunological markers to predict clinical outcomes, and the ability of tumors to escape immune recognition and destruction as challenges to the development and application of immunotherapy. In this paper, we have reviewed the mechanisms underlying immune unresponsiveness to TAAs and strategies to overcome this unresponsiveness in the humoral and cellular immune responses, highlighting findings from different antigenic systems to prove the validity of these strategies. Additionally, we have addressed limitations to TAA-targeting immunotherapy as a result of the genetic instability of tumor cells, and have discussed strategies to overcome this limitation by targeting immunotherapy to molecules implicated in tumor-associated angiogenesis. Lastly, we have concluded by indicating the need to refine the implementation of clinical trials of immunotherapy, and to emphasize combination therapies to counteract the multiple tumor escape mechanisms.
近年来，免疫疗法作为化疗和放疗的替代方法用于治疗恶性疾病，受到越来越多的关注。这种关注源于多种因素，包括免疫监视理论的复兴、明确且结构特征清楚的人类肿瘤相关抗原（TAA）的可得性、我们对诱导和维持免疫反应所需分子途径理解的进展，以及生成TAA特异性细胞毒性T淋巴细胞（CTL）和单克隆抗体（mAb）作为免疫探针的方法学进展。然而，与在动物模型系统中TAA特异性免疫疗法获得的阳性结果相反，患者的临床反应令人失望。通常，免疫反应与临床反应不相关。对这种二分法潜在机制的分析已确定，TAA的低免疫原性、缺乏预测临床结果的免疫标志物，以及肿瘤逃避免疫识别和破坏的能力是免疫疗法开发和应用面临的挑战。在本文中，我们综述了对TAA免疫无反应性的潜在机制以及在体液和细胞免疫反应中克服这种无反应性的策略，强调了来自不同抗原系统的研究结果以证明这些策略的有效性。此外，我们讨论了由于肿瘤细胞的基因不稳定性导致的TAA靶向免疫疗法的局限性，并探讨了通过将免疫疗法靶向与肿瘤相关血管生成有关的分子来克服这一局限性的策略。最后，我们得出结论，指出需要完善免疫疗法临床试验的实施，并强调联合疗法以对抗多种肿瘤逃逸机制。
