CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: The success of immune checkpoint inhibitors has revolutionized cancer treatment options and triggered development of new complementary immunotherapeutic strategies, including T-cell co-stimulatory molecules, such as glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). BMS-986156 is a fully agonistic human immunoglobulin G subclass 1 monoclonal antibody targeting GITR. We recently presented the clinical data for BMS-986156 with or without nivolumab, which demonstrated no compelling evidence of clinical activity in patients with advanced solid tumors. Here, we further report the pharmacodynamic (PD) biomarker data from this open-label, first-in-human, phase I/IIa study of BMS-986156 nivolumab in patients with advanced solid tumors (NCT02598960). MATERIALS AND METHODS: We analyzed PD changes of circulating immune cell subsets and cytokines in peripheral blood or serum samples collected from a dataset of 292 patients with solid tumors before and during treatment with BMS-986156 nivolumab. PD changes in the tumor immune microenvironment were measured by immunohistochemistry and a targeted gene expression panel. RESULTS: BMS-986156 + nivolumab induced a significant increase in peripheral T-cell and natural killer (NK) cell proliferation and activation, accompanied by production of proinflammatory cytokines. However, no significant changes in expression of CD8A, programmed death-ligand 1, tumor necrosis factor receptor superfamily members, or key genes linked with functional parameters of T and NK cells were observed in tumor tissue upon treatment with BMS-986156. CONCLUSIONS: Despite the robust evidence of peripheral PD activity of BMS-986156, with or without nivolumab, limited evidence of T- or NK cell activation in the tumor microenvironment was observed. The data therefore explain, at least in part, the lack of clinical activity of BMS-986156 with or without nivolumab in unselected populations of cancer patients.