Geils Christian, Kathrein Katie L
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA.
J Gene Med. 2024 Dec;26(12):e70000. doi: 10.1002/jgm.70000.
Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically "cold" to "hot." Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.
免疫疗法是一类通过操控免疫系统来实现治疗益处的疗法。这些治疗方法包括免疫检查点抑制剂、过继性细胞疗法和疫苗。对于许多血液系统恶性肿瘤而言，免疫疗法已成为一种重要的治疗组成部分。然而，这种成功尚未在实体瘤中得到复制，因为实体瘤会形成先进的物理和分子机制来抑制和逃避免疫破坏。尽管如此，细胞因子免疫疗法通过向肿瘤传递促炎免疫信号，从而将其从免疫“冷”肿瘤转变为“热”肿瘤，为克服这些障碍提供了一种潜在的解决方案。白细胞介素-12（IL-12）是最有效的促炎细胞因子之一，最初就是为此目的而进行研究的。然而，最初在小鼠和人类中进行的全身性给予IL-12的研究导致了与脱靶免疫激活相关的危险免疫毒性。因此，最近的研究采用了先进的细胞和分子工程方法来降低IL-12的毒性，同时提高或维持其疗效，以便其有效剂量能够被人体耐受。本综述重点介绍了这些进展，并确定了有前景的未来研究方向。
