Msaouel Pavlos, Genovese Giannicola, Gao Jianjun, Sen Suvajit, Tannir Nizar M
Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Exelixis Inc., Alameda, California, USA.
Expert Opin Ther Targets. 2021 Feb;25(2):141-151. doi: 10.1080/14728222.2021.1869212. Epub 2020 Dec 31.
: Immune checkpoint inhibitors (ICI) have shown great promise in a wide spectrum of malignancies. However, responses are not always durable, and this mode of treatment is only effective in a subset of patients. As such, there exists an unmet need for novel approaches to bolster ICI efficacy.: We review the role of the Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases in promoting tumor-induced immune suppression and discuss the benefits that may be derived from combining ICI with TAM kinase-targeted tyrosine kinase inhibitors. We searched the MEDLINE Public Library of Medicine (PubMed) and EMBASE databases and referred to ClinicalTrials.gov for relevant ongoing studies.: Targeting of TAM kinases may improve the efficacy of immune checkpoint blockade. However, it remains to be determined whether this effect will be better achieved by the selective targeting of each TAM receptor, depending on the context, or by multi-receptor TAM inhibitors. Triple inhibition of all TAM receptors is more likely to be associated with an increased risk for adverse events. Clinical trial designs should use high-resolution clinical endpoints and proper control arms to determine the synergistic effects of combining TAM inhibition with immune checkpoint blockade.
免疫检查点抑制剂（ICI）在多种恶性肿瘤中显示出巨大潜力。然而，疗效并不总是持久的，且这种治疗方式仅对部分患者有效。因此，对于提高ICI疗效的新方法仍存在未满足的需求。
我们综述了酪氨酸蛋白激酶受体3（Tyro3）、Axl和Mer（TAM）受体酪氨酸激酶在促进肿瘤诱导的免疫抑制中的作用，并讨论了将ICI与靶向TAM激酶的酪氨酸激酶抑制剂联合使用可能带来的益处。我们检索了医学在线数据库（MEDLINE）的医学图书馆（PubMed）和EMBASE数据库，并参考ClinicalTrials.gov获取相关正在进行的研究。
靶向TAM激酶可能会提高免疫检查点阻断的疗效。然而，根据具体情况，是通过选择性靶向每个TAM受体，还是通过多受体TAM抑制剂能更好地实现这种效果，仍有待确定。对所有TAM受体的三联抑制更可能与不良事件风险增加相关。临床试验设计应使用高分辨率的临床终点和合适的对照臂，以确定联合TAM抑制与免疫检查点阻断的协同效应。
