Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs. This more beneficial tumor response-to-toxicity profile stems from distinct mechanisms of action that restore tumor-induced immune deficiency selectively in the tumor microenvironment, here termed “immune normalization,” which has led to its FDA approval in more than 10 cancer indications and facilitated its combination with different therapies. In this article, we wish to highlight the principles of immune normalization and learn from it, with the ultimate goal to guide better designs for future cancer immunotherapies.
利用抗肿瘤免疫反应一直是癌症免疫治疗的核心策略。一个多世纪以来，研究主要集中于增强人类用于清除病毒和细菌等入侵者的免疫激活机制。这种“免疫增强”策略常导致客观缓解率较低，且免疫相关不良事件频发。然而在过去十年中，针对B7-H1/PD-1通路的癌症免疫疗法（抗PD疗法）在显著减少免疫相关不良事件的同时，为患者实现了更高的客观缓解率。这种更优化的肿瘤反应-毒性特征源于独特的作用机制——选择性地在肿瘤微环境中恢复肿瘤诱导的免疫缺陷，即“免疫正常化”。该疗法已获得FDA批准用于10余种癌症适应症，并促进了其与不同疗法的联合应用。本文旨在阐明免疫正常化的原理并从中汲取经验，以期指导未来癌症免疫疗法的优化设计。
A Paradigm Shift in Cancer Immunotherapy: From Enhancement to Normalization
肿瘤(癌症)患者之家