Dougan Michael, Dranoff Glenn, Dougan Stephanie K
Division of Gastroenterology and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Harvard Medical School, Harvard University, Boston, Massachusetts 02115, USA.
Annu Rev Cancer Biol. 2019 Mar;3:55-75. doi: 10.1146/annurev-cancerbio-030518-055552. Epub 2018 Nov 7.
Blocking antibodies to the immune checkpoint receptors or their ligands have revolutionized the treatment of diverse malignancies. Many tumors are recognized by adaptive immunity, but these adaptive responses can be inhibited by immunosuppressive mechanisms within the tumor, often through pathways outside of the currently targeted checkpoints. For this reason, only a minority of cancer patients achieve durable responses to current immunotherapies. Multiple novel approaches strive to expand immunotherapy's reach. These may include targeting alternative immune checkpoints. However, many investigational strategies look beyond checkpoint blockade. These include cellular therapies to bypass endogenous immunity and efforts to stimulate new adaptive antitumor responses using vaccines, adjuvants, and combinations with cytotoxic therapy, as well as strategies to inhibit innate immune suppression and modulate metabolism within the tumor microenvironment. The challenge for immunotherapy going forward will be to select rational strategies for overcoming barriers to effective antitumor responses from the myriad possible targets.
针对免疫检查点受体或其配体的阻断性抗体彻底改变了多种恶性肿瘤的治疗方式。许多肿瘤可被适应性免疫识别，但这些适应性反应可能会受到肿瘤内免疫抑制机制的抑制，通常是通过当前靶向检查点之外的途径。因此，只有少数癌症患者能对当前的免疫疗法产生持久反应。多种新方法致力于扩大免疫疗法的适用范围。这些方法可能包括靶向其他免疫检查点。然而，许多研究策略并不局限于检查点阻断。这些策略包括通过细胞疗法绕过内源性免疫，以及利用疫苗、佐剂和与细胞毒性疗法联合使用来刺激新的适应性抗肿瘤反应的努力，还有抑制先天性免疫抑制和调节肿瘤微环境内代谢的策略。未来免疫疗法面临的挑战将是从众多可能的靶点中选择合理的策略来克服有效抗肿瘤反应的障碍。
