Division of Thoracic Tumor Multimodality Treatment, Cancer Center & State Key Laboratory of Biotherapy, and The National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, PR China.
Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610041, Sichuan, PR China.
Signal Transduct Target Ther. 2024 May 22;9(1):126. doi: 10.1038/s41392-024-01826-z.
Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
免疫疗法以抗 PD-(L)1 和抗 CTLA-4 抑制剂为代表，彻底改变了癌症治疗，但与耐药性和毒性相关的挑战仍然存在。由于免疫肿瘤学的进步，越来越多的新型免疫调节靶点和机制被揭示出来，相关疗法有望在可预见的未来改善临床免疫治疗。因此，了解全貌很重要。在这篇综述中，我们分析和总结了目前临床前和转化机制研究、药物开发和临床试验的现状，这些研究带来了新一代的药理学免疫调节抗癌药物和药物候选物，超越了经典的免疫检查点抑制剂。随着癌症免疫生物学的进一步阐明和抗体工程的进步，针对其他抑制性免疫检查点的药物，包括 LAG-3、TIM-3、TIGIT、CD47 和 B7 家族成员，正在成为癌症免疫治疗研究和发现的重要组成部分，结构和功能优化的新型抗 PD-(L)1 和抗 CTLA-4 药物以及 T 细胞共刺激分子的激动剂也是如此。以双特异性 T 细胞衔接器为例，新出现的针对免疫调节分子的双特异性和多特异性抗体可以提供相当大的临床获益。下一代药物还包括免疫表观遗传学药物和细胞因子治疗药物。细胞疗法、癌症疫苗和溶瘤病毒不在本综述范围内。这篇全面的综述可能有助于进一步开发和最快实现有效的免疫肿瘤学模式的临床应用，使患者受益。
