摘要
As a result of recent breakthroughs in cancer immunotherapies, unprecedented and durable remission, and even cure, has been reported in some patients. Importantly, this progress has been achieved, not by the induction of immunity, but by the delivery of immunity in the form of engineered antibodies （cAbs） or effector T cells. However, these single-target technologies have failed to result in a therapeutic effect in some patients, and evidence suggests that further advances depend on an effective strategy for coping with cancer heterogeneity and dynamics. A synthetic immunity （SI） strategy is proposed to achieve this goal. The fundamental basis of SI involves the generation of a panel of cAbs and antibody-retargeted CTLs designed to destroy all cell lineages of a cancer with high specificity. This goal can be achieved only when the composition of the cAbs is determined using a systematic approach, i.e., selecting the antigens targeted by the cAbs based on an epitope-tree illustrating the clonal antigen architecture of the cancer. Integration of technologies that increase the epitope breadth, cAb affinity and T cell activity will further enhance the efficacy of SI. Using DNA vectors to express the eAbs will be a safe, effective and affordable solution.
近年来,肿瘤免疫治疗取得了令人瞩目的重大突破,采用过继免疫技术输入工程抗体或工程效应T细胞,一些接受治疗的患者获得持久的缓解甚至痊愈.然而,这些单靶点治疗技术对部分患者没有疗效.有证据表明,肿瘤的异质性(heterogeneity)和不断进化(evolving)的特性是造成治疗失败的原因,只有发展出针对这些肿瘤特性的新方法,才能实现新的突破.本文提出用合成免疫策略(synthetic immunity,SI)来实现这一目标.SI的原则是通过制备一组工程抗体和抗体重新定向的细胞毒T淋巴细胞(antibody-retargeted cytotoxic T cells)高度特异性地杀死全部肿瘤细胞系而达到根治的目的.要实现这一目标,只能通过系统化方法来选择组合工程抗体,具体是建立一个肿瘤抗原系统树(tumor epitope-tree)来确定肿瘤细胞系及其抗原的系统构成,然后选择"树干或主要分杈"上的"抗原靶点组"来进行过继免疫治疗,最终消灭所有肿瘤细胞系.同时结合其他技术如扩大抗原表位数量、提高抗体亲和力和T细胞活性等,可以进一步提高SI的效率.此外,用非病毒DNA基因载体在体内生产工程抗体将是一个安全、有效和经济的解决方案.
基金
supported by the government funds of Shenzhen,China(SFG 2012.566 and SKC 2012.237)
