Parker Institute of Cancer Immunotherapy, 1 Letterman Drive, San Francisco, CA, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA, 94129, USA.
Genome Med. 2018 Oct 31;10(1):79. doi: 10.1186/s13073-018-0588-4.
For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cancer immunotherapies. Pathways targeted for therapeutic intervention in autoimmune diseases can be modulated in the opposite sense in malignancy and infectious disease. We discuss the basic principles of the immune response, how these are co-opted in chronic infection and malignancy, and how these can be harnessed to treat disease. T cells are at the center of immunotherapy. We consider the complexity of T cell functional subsets, differentiation states, and extrinsic and intrinsic influences in the design, success, and lessons from immunotherapies. The integral role of checkpoints in the immune response is highlighted by the rapid advances in FDA approvals and the use of therapeutics that target the CTLA-4 and PD-1/PD-L1 pathways. We discuss the distinct and overlapping mechanisms of CTLA-4 and PD-1 and how these can be translated to combination immunotherapy treatments. Finally, we discuss how the successes and challenges in cancer immunotherapies, such as the collateral damage of immune-related adverse events following checkpoint inhibition, are informing treatment of autoimmunity, infection, and malignancy.
至少 300 年来，人们一直致力于靶向免疫系统以改善人类健康。几十年来，人们一直在努力推进抗感染和自身免疫的免疫疗法，为当前癌症免疫疗法的蓬勃发展铺平了道路。在自身免疫性疾病中靶向治疗干预的途径在恶性肿瘤和传染病中可以朝着相反的方向调节。我们讨论了免疫反应的基本原理，这些原理如何在慢性感染和恶性肿瘤中被篡夺，以及如何利用这些原理来治疗疾病。T 细胞是免疫疗法的核心。我们考虑了 T 细胞功能亚群、分化状态以及设计、成功和免疫疗法经验中的外在和内在影响的复杂性。检查点在免疫反应中的重要作用，突出体现在 FDA 批准的快速进展和使用靶向 CTLA-4 和 PD-1/PD-L1 途径的治疗药物上。我们讨论了 CTLA-4 和 PD-1 的不同和重叠机制，以及如何将其转化为联合免疫治疗。最后，我们讨论了癌症免疫疗法的成功和挑战，例如检查点抑制后免疫相关不良事件的附带损害，如何为自身免疫、感染和恶性肿瘤的治疗提供信息。
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