Schaub John, Tang Shou-Ching
Woodlands Medical Specialists, 4724 N Davis Hwy, Pensacola, FL, 32503, USA.
LSU-LCMC Cancer Center, LSU School of Medicine, 1700 Tulane Avenue, Room 510, New Orleans, LA, 70112, USA.
Clin Exp Med. 2025 Jan 21;25(1):43. doi: 10.1007/s10238-024-01546-2.
Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with the discovery of CTLA-4, PD-1 and PD-L1 and the roles in inhibiting immune function and tumor evasion of anti-tumor immune response. Following the approval of the first checkpoint inhibitor ipilimumab against CTLA-4 in melanoma in 2011, there has been a rapid development of tumor immunotherapy. Furthermore, additional positive and negative molecules among the T-cell regulatory systems have been identified that that function to fine tune the stimulatory or inhibitory immune cells and modulate their functions (checkpoint modulators). Many strategies are being explored to target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines and molecules involved in tumor tolerance and microbiome. Similar to agents that target checkpoint modulators, these newer targets have the potential to synergize with other classes of immunotherapeutic agents and importantly may overcome the resistance to other immunotherapies. In order to better understand the mechanism of action of all major classes of immunotherapy, design clinical trials taking advantage of different types of immunotherapeutic agents and use them rationally in clinical practice either in combination or in sequence, we propose the group all immunotherapies into three generations: with CTLA-4, PD-1 and PD-L1 inhibitors as the first generation, agents that target the checkpoint modulators as the second generation, while those that target TME as the third generation. This review discusses all three generations of immunotherapy in oncology, their mechanism of actions, major clinical trial results and indication, strategies for future clinical trial designs and rational clinical applications.
在过去二十年中，随着细胞毒性T淋巴细胞相关抗原4（CTLA-4）、程序性死亡受体1（PD-1）和程序性死亡配体1（PD-L1）的发现以及它们在抑制免疫功能和肿瘤逃避抗肿瘤免疫反应中的作用，抗肿瘤免疫疗法得以重新发现并焕发生机。2011年，首个针对黑色素瘤中CTLA-4的检查点抑制剂伊匹单抗获批后，肿瘤免疫疗法迅速发展。此外，T细胞调节系统中还发现了其他正负性分子，它们的作用是微调刺激性或抑制性免疫细胞并调节其功能（检查点调节剂）。目前正在探索许多策略来靶向巨噬细胞、自然杀伤细胞、细胞毒性T细胞、成纤维细胞、内皮细胞、参与肿瘤耐受的细胞因子和分子以及微生物群。与靶向检查点调节剂的药物类似，这些新靶点有可能与其他类别的免疫治疗药物协同作用，重要的是可能克服对其他免疫疗法的耐药性。为了更好地理解所有主要类别的免疫疗法的作用机制，设计利用不同类型免疫治疗药物的临床试验，并在临床实践中合理联合或序贯使用它们，我们建议将所有免疫疗法分为三代：以CTLA-4、PD-1和PD-L1抑制剂为第一代，靶向检查点调节剂的药物为第二代，而靶向肿瘤微环境的药物为第三代。本综述讨论了肿瘤学中的三代免疫疗法、它们的作用机制、主要临床试验结果和适应症、未来临床试验设计策略以及合理的临床应用。
