Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan St., 2N35, Portland, OR, 97213, USA.
Molecular Microbiology and Immunology Department, Oregon Health and Science University, Portland, OR, 97239, USA.
BioDrugs. 2018 Jun;32(3):221-231. doi: 10.1007/s40259-018-0277-2.
Recent advancements in T-cell biology and antibody engineering have opened doors to significant improvements in cancer immunotherapy. Initial success with monoclonal antibodies targeting key receptors that inhibit T-cell function such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-1) have demonstrated the potency of this new class of therapy, highlighted by long-term complete responses for metastatic cancers once thought incurable. However, only a subset of patients responds to checkpoint blockade because of a multitude of factors, including an immunosuppressive tumor microenvironment and the mutational burden of the cancer. Novel antibodies, as well as ligand-immunoglobulin fusion proteins that target costimulatory immune receptors, are being developed and tested in clinical trials to further enhance the anti-tumor immune response. Many of these costimulatory receptors are in the tumor necrosis factor receptor superfamily (TNFRSF) and are expressed on multiple immune cell types, including inhibitory cells. While TNFRSFs signal through common pathways, the outcome of targeting different receptors depends on the functional status of the cell types expressing the relevant receptors. In this review, we discuss the current state of targeted costimulatory immunotherapy.
近年来，T 细胞生物学和抗体工程的进展为癌症免疫疗法的重大改进开辟了道路。最初成功地使用单克隆抗体靶向抑制 T 细胞功能的关键受体，如细胞毒性 T 淋巴细胞抗原 4（CTLA-4）和程序性死亡配体 1（PD-1），证明了这种新型治疗方法的效力，转移性癌症的长期完全缓解突出了这一点，这些癌症曾经被认为是无法治愈的。然而，由于多种因素，包括免疫抑制性肿瘤微环境和癌症的突变负担，只有一部分患者对检查点阻断有反应。新型抗体以及针对共刺激免疫受体的配体-免疫球蛋白融合蛋白正在临床试验中进行开发和测试，以进一步增强抗肿瘤免疫反应。这些共刺激受体中的许多都属于肿瘤坏死因子受体超家族（TNFRSF），并在多种免疫细胞类型上表达，包括抑制性细胞。虽然 TNFRSF 通过共同途径发出信号，但靶向不同受体的结果取决于表达相关受体的细胞类型的功能状态。在这篇综述中，我们讨论了靶向共刺激免疫疗法的现状。
