Wendtner C M, Kofler D M, Mayr C, Bund D, Hallek M
Medical Clinic III, Klinikum Grosshadern Medical Center, München, German.
Leuk Lymphoma. 2004 May;45(5):897-904. doi: 10.1080/10428190310001638896.
Despite recent advances, chronic lymphocytic leukemia (CLL) as the most common leukemia remains a largely incurable disease. Modern treatment options include novel drugs like purine analogues, monoclonal antibodies and transplantation strategies. Moreover, gene transfer of immunostimulatory molecules is another, but still experimental approach that can be used to potentiate immune responses against leukemic cells. CD40 ligand (CD40L) was shown to be a promising molecule for immunotherapy of B-CLL playing a critical role in immune activation. However, CLL B cells are resistant to transduction with most currently available vector systems. Improving the efficiency and specificity of gene vectors is critical for the success of gene therapy in this area. Using replication defective adenovirus encoding CD40L (Ad-CD40L), immunologic and clinical responses were seen in CLL patients after infusion of autologous Ad-CD40L-CLL cells in a recent phase I trial. Due to the immunogenic nature of adenovirus vectors, alternative vector systems are currently explored. Recombinant adeno-associated virus (rAAV) was shown to enable efficient transduction of primary B-CLL cells. By use of a library of AAV clones with randomly modified capsids, receptor-targeting mutants with a tropism for CLL cells can be selected. Furthermore, helper-virus free Epstein-Barr virus (EBV)-based gene transfer vectors hold promise for development of CLL-targeted vaccines after remaining safety issues will be resolved. Herpes simplex virus (HSV)-based vectors, especially HSV amplicons, have favorable features for B-CLL gene transfer including high transduction efficiency, ability to infect postmitotic cells and a large packaging capacity. The challenge for the future will be to transfer these alternative vector systems into clinic and allow the detection of a CLL-specific immune response by use of defined tumor antigens. This will make it possible to establish the potential clinical role of gene therapy for CLL patients.
尽管近年来取得了进展，但作为最常见白血病的慢性淋巴细胞白血病（CLL）在很大程度上仍然是一种无法治愈的疾病。现代治疗选择包括嘌呤类似物、单克隆抗体等新型药物以及移植策略。此外，免疫刺激分子的基因转移是另一种仍处于实验阶段的方法，可用于增强针对白血病细胞的免疫反应。CD40配体（CD40L）被证明是B-CLL免疫治疗的一个有前景的分子，在免疫激活中起关键作用。然而，CLL B细胞对目前大多数可用载体系统的转导具有抗性。提高基因载体的效率和特异性对于该领域基因治疗的成功至关重要。在最近的一项I期试验中，通过输注自体Ad-CD40L-CLL细胞，CLL患者在使用编码CD40L的复制缺陷型腺病毒（Ad-CD40L）后出现了免疫和临床反应。由于腺病毒载体的免疫原性，目前正在探索替代载体系统。重组腺相关病毒（rAAV）已被证明能够有效地转导原发性B-CLL细胞。通过使用具有随机修饰衣壳的AAV克隆文库，可以选择对CLL细胞具有嗜性的受体靶向突变体。此外，在解决剩余的安全问题后，基于无辅助病毒的爱泼斯坦-巴尔病毒（EBV）的基因转移载体有望用于开发针对CLL的疫苗。基于单纯疱疹病毒（HSV）的载体，尤其是HSV扩增子，具有有利于B-CLL基因转移的特性包括高转导效率、感染有丝分裂后细胞的能力和大包装容量。未来的挑战将是将这些替代载体系统应用于临床，并通过使用确定的肿瘤抗原来检测CLL特异性免疫反应。这将有可能确立基因治疗对CLL患者的潜在临床作用。
