Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Semin Oncol. 2012 Jun;39(3):305-10. doi: 10.1053/j.seminoncol.2012.02.013.
Although cellular immunotherapy based on autolgous dendritic cells (DCs) targeting antigens expressed by metastatic cancer has demonstrated clinical efficacy, the logistical challenges in generating an individualized cell product create an imperative to develop alternatives to DC-based cancer vaccines. Particularly attractive alternatives include in situ delivery of antigen and activation signals to resident antigen-presenting cells (APCs), which can be achieved by novel fusion molecules targeting the mannose receptor and by recombinant viral vectors expressing the antigen of interest and capable of infecting DCs. A particular challenge in the use of viral vectors is the well-appreciated clinical obstacles to their efficacy, specifically vector-specific neutralizing immune responses. Because heterologous prime and boost strategies have been demonstrated to be particularly potent, we developed two novel recombinant vectors based on alphaviral replicon particles and a next-generation adenovirus encoding an antigen commonly overexpressed in many human cancers, carcinoembryonic antigen (CEA). The rationale for developing these vectors, their unique characteristics, the preclinical studies and early clinical experience with each, and opportunities to enhance their effectiveness will be reviewed. The potential of each of these potent recombinant vectors to efficiently generate clinically active anti-tumor immune response alone, or in combination, will be discussed.
虽然基于针对转移性癌症表达抗原的自体树突状细胞 (DC) 的细胞免疫疗法已显示出临床疗效，但生成个体化细胞产品的后勤挑战要求开发替代基于 DC 的癌症疫苗的方法。特别有吸引力的替代方法包括原位递送至驻留抗原呈递细胞 (APC) 的抗原和激活信号，这可以通过靶向甘露糖受体的新型融合分子和表达感兴趣抗原并能够感染 DC 的重组病毒载体来实现。在使用病毒载体时，一个特别的挑战是它们的疗效存在众所周知的临床障碍，特别是载体特异性中和免疫反应。因为已经证明异源初免和加强策略特别有效，我们开发了两种基于α病毒复制子颗粒和编码在许多人类癌症中过度表达的抗原的新一代腺病毒的新型重组载体，即癌胚抗原 (CEA)。将讨论开发这些载体的原理、它们的独特特征、每种载体的临床前研究和早期临床经验，以及增强它们效果的机会。将讨论这些有效重组载体单独或联合使用时有效产生临床活性抗肿瘤免疫反应的潜力。
