Horn Lucas A, Ciavattone Nicholas G, Atkinson Ryan, Woldergerima Netsanet, Wolf Julia, Clements Virginia K, Sinha Pratima, Poudel Munanchu, Ostrand-Rosenberg Suzanne
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
Oncotarget. 2017 Aug 3;8(35):57964-57980. doi: 10.18632/oncotarget.19865. eCollection 2017 Aug 29.
Bi-specific T cell engagers (BiTEs) activate T cells through CD3 and target activated T cells to tumor-expressed antigens. BiTEs have shown therapeutic efficacy in patients with liquid tumors; however, they do not benefit all patients. Anti-tumor immunity is limited by Programmed Death 1 (PD1) pathway-mediated immune suppression, and patients who do not benefit from existing BiTES may be non-responders because their T cells are anergized via the PD1 pathway. We have designed a BiTE that activates and targets both T cells and NKT cells to PDL1 cells. studies demonstrate that the CD3xPDL1 BiTE simultaneously binds to both CD3 and PDL1, and activates healthy donor CD4 and CD8 T cells and NKT cells that are specifically cytotoxic for PDL1 tumor cells. Cancer patients' PBMC are also activated and cytotoxic, despite the presence of myeloid-derived suppressor cells. The CD3xPDL1 BiTE significantly extends the survival time and maintains activated immune cell levels in humanized NSG mice reconstituted with human PBMC and carrying established human melanoma tumors. These studies suggest that the CD3xPDL1 BiTE may be efficacious for patients with PDL1 solid tumors, in combination with other immunotherapies that do not specifically neutralize PD1 pathway-mediated immune suppression.
双特异性T细胞衔接器（BiTEs）通过CD3激活T细胞，并将活化的T细胞靶向肿瘤表达的抗原。BiTEs在实体瘤患者中已显示出治疗效果；然而，并非所有患者都能从中受益。抗肿瘤免疫受到程序性死亡1（PD1）通路介导的免疫抑制的限制，那些无法从现有BiTEs中获益的患者可能是无反应者，因为他们的T细胞通过PD1通路而失能。我们设计了一种BiTE，它能将T细胞和自然杀伤性T细胞（NKT细胞）都激活并靶向至程序性死亡配体1（PDL1）细胞。研究表明，CD3xPDL1 BiTE能同时与CD3和PDL1结合，并激活对PDL1肿瘤细胞具有特异性细胞毒性的健康供体CD4和CD8 T细胞以及NKT细胞。尽管存在髓系来源的抑制细胞，但癌症患者的外周血单核细胞（PBMC）也能被激活并具有细胞毒性。在用人PBMC重建并携带已建立的人黑色素瘤肿瘤的人源化NSG小鼠中，CD3xPDL1 BiTE显著延长了生存时间并维持了活化免疫细胞水平。这些研究表明，CD3xPDL1 BiTE可能对PDL1实体瘤患者有效，可与其他不能特异性中和PD1通路介导的免疫抑制的免疫疗法联合使用。
