CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Curr Top Med Chem. 2019;19(3):180-185. doi: 10.2174/1568026619666190308131805.
Oncology immunotherapy has gained significant advances in recent years and benefits cancer patients with superior efficacy and superior clinical responses. Currently over ten immune checkpoint antibodies targeting CTLA-4 and PD-1/PD-L1 have received regulatory approval worldwide and over thousands are under active clinical trials. However, compared to the rapid advance of Monoclonal Antibody (mAb), studies on immunotherapeutic small molecules have far lagged behind. Small molecule immunotherapy not only can target immunosuppressive mechanisms similar to mAbs, but also can stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAbs are unable to access. Therefore, small molecule immunotherapy can provide an alternative treatment modality either alone or complementary to or synergistic with extracellular checkpoint mAbs to address low clinical response and drug resistance. Fortunately, remarkable progress has achieved recently in the pursuit of small molecule immunotherapy. This review intends to provide a timely highlight on those clinically investigated small molecules targeting PD-1/PD-L1, IDO1, and STING. The most advanced IDO1 inhibitor epacadostat have been aggressively progressed into multiple clinical testings. Small molecule PD-1/PD-L1 inhibitors and STING activators are still in a premature state and their decisive application needs to wait for the ongoing clinical outcomes. Since no small molecule immunotherapy has been approved yet, the future research should continue to focus on discovery of novel small molecules with distinct chemo-types and higher potency, identification of biomarkers to precisely stratify patients, as well as validation of many other immune-therapeutic targets, such as LAG3, KIRs, TIM-3, VISTA, B7-H3, and TIGIT.
肿瘤免疫疗法近年来取得了重大进展，为癌症患者带来了更好的疗效和更优的临床反应。目前，全球已有超过 10 种针对 CTLA-4 和 PD-1/PD-L1 的免疫检查点抗体获得监管批准，还有上千种正在进行积极的临床试验。然而，与单克隆抗体（mAb）的快速发展相比，免疫治疗小分子的研究远远落后。小分子免疫疗法不仅可以针对与 mAb 相似的免疫抑制机制，还可以刺激先天或适应性免疫细胞中检查点蛋白下游的细胞内途径，而 mAb 无法到达这些途径。因此，小分子免疫疗法可以单独或与细胞外检查点 mAb 互补或协同提供一种替代治疗方式，以解决临床反应率低和耐药性问题。幸运的是，最近在小分子免疫疗法的研究方面取得了显著进展。本综述旨在及时介绍那些针对 PD-1/PD-L1、IDO1 和 STING 的临床研究小分子。最先进的 IDO1 抑制剂 epacadostat 已被积极推进到多项临床试验中。小分子 PD-1/PD-L1 抑制剂和 STING 激活剂仍处于早期阶段，其决定性应用需要等待正在进行的临床结果。由于目前尚无小分子免疫疗法获得批准，未来的研究应继续专注于发现具有独特化学结构和更高效力的新型小分子，鉴定能够准确分层患者的生物标志物，以及验证许多其他免疫治疗靶点，如 LAG3、KIRs、TIM-3、VISTA、B7-H3 和 TIGIT。
