摘要：治疗性肿瘤疫苗通过激活肿瘤抗原特异性T细胞，理论上可以在降低不良反应的同时实现强大且持久的抗 肿瘤疗效。但目前对抗肿瘤免疫反应的理解仍然十分有限，虽然研究者尝试了多种抗原筛选策略和制剂配方，仍 未能在临床试验中取得满意的结果。由于肿瘤异质性与免疫抑制现象广泛存在，开发以新抗原为基础的个体化肿瘤 疫苗、加强多种免疫疗法的联合应用是未来的发展方向。肿瘤疫苗在膀胱癌治疗领域的应用已初见成效，多项临 床研究正在持续进行。本文对肿瘤疫苗的抗原筛选、制剂类型以及最近的研究成果和发展方向作一综述。

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丁炜宏,徐可. 治疗性肿瘤疫苗及其在膀胱癌中的应用进展[J]. 泌尿外科杂志（电子版）,2021,13(3):33-40. DOI:10.3969/j.issn.1674-7410.2021.03.008.

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治疗性肿瘤疫苗是一种能够靶向肿瘤抗原，从 而放大抗肿瘤免疫应答，达到治疗肿瘤目的的一种 药物。其基本原理是在体内或体外使用肿瘤抗原刺 激抗原提呈细胞 （antigen presenting cell，APC）， APC 以 抗 原 肽 -主 要 组 织 相 容 性 复 合 体 [（major histocompatibility complex，MHC），又称人类白细 胞抗原 （human leukocyte antigen，HLA） ]的形式 将抗原提呈给 T 细胞，最终诱导抗原特异性 T 细胞 应答[1] 。经 MHCⅠ、MHCⅡ提呈的抗原通常分别激 活 CD8 + T[细胞毒性 T 细胞 （cytotoxic T lymphocyte，CTL）]、CD4+ T[辅助T细胞 （T helper cells， Th） ]，虽然 CD4+ 、CD8+ T 细胞在抗肿瘤免疫中的 作用还存在争议[2] ，但目前多数研究都将 CD8+ T细胞 的活性作为疫苗疗效的检验标准。 

肿瘤疫苗的活性成分包括肿瘤抗原和免疫佐 剂。选择合适的疫苗抗原是产生良好抗肿瘤免疫的 基石。免疫佐剂通过活化 APC 以辅助增强抗原提呈 和共刺激信号，一般是 APC 表面的模式识别受体的 激动剂[3] 。肿瘤抗原和佐剂可以通过肽/蛋白、肿瘤 细胞、APC、病毒、核酸 5 种运载方式制成肿瘤疫 苗。虽然迄今为止已经在动物模型和临床试验中尝 试了大量抗原、佐剂、制剂类型、给药策略，但每 种疫苗成分各有利弊，最有效的疫苗系统结构尚无 定论。 

因此，本文将对肿瘤疫苗的抗原类型、制剂类 型以及肿瘤疫苗在膀胱癌治疗中的临床应用进行综 述，并展望肿瘤疫苗未来的发展。

1 肿瘤疫苗的抗原类型

2 肿瘤疫苗的制剂类型

3 肿瘤疫苗在膀胱癌中的临床应用

4 总结与展望

4 总结与展望 

肿瘤疫苗直接激活机体自身的免疫应答，是最 具前景的癌症疗法之一。根据既往的临床经验，靶 向单一肿瘤抗原的免疫疗法不足以应对广泛存在的 免疫抑制和逃逸现象[35] ，有必要为此开发更加广泛的 抗原表位。虽然大多数研究和预测算法都将注意力 集中在 MHCⅠ限制性表位及 CD8+ T细胞的细胞毒作 用，但 CD4+ T 细胞在免疫反应中的作用不可忽视。 多个临床前和临床研究发现，根据 MHCⅠ亲和力预 测算法筛选出的抗原肽却能诱导出显著的 CD4+ T 细 胞反应[36-39] 。临床前研究已经证实，CD4+ T可以分泌 IFN-γ、参与强化 CD8+ T 细胞反应和抗体反应，甚 至可以通过颗粒胞吐或 Fas-Fas 配体途径直接发挥 细胞毒性[39- 40] 。因此，同时靶向 MHCⅠ与 MHCⅡ 限制性表位的多价疫苗或可诱导更大强度的抗肿瘤 免疫。除此之外，靶向 TAA 和 TSA、SNV 和 indel 突变等多种类型的抗原组合也是值得尝试的研发方 向[41] 。提高测序技术的敏感度、优化现有的预测算 法、开发更精确的 MHCⅡ预测算法[8] ，将有助于扩 大新抗原备选库，推动个体化肿瘤疫苗的广泛应 用。综上，虽然细胞应答与临床应答之间仍有重重 困难需要克服，但随着理论和技术的发展以及多种 治疗方法的联合应用，治疗性肿瘤疫苗有望成为最 安全、最有效、最持久的癌症疗法之一。

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