Zieger et al. demonstrated that in patients with r/r B-cell precursor ALL, 28-day continuous infusion with AMG 562 (a CD19xCD3 bispecific antibody) induced T cell exhaustion, which was rescued by treatment-free intervals. Continuous AMG 562 exposure induced progressive loss of T cell function, with increased inhibitory receptor and TOX expression, decreased cytokine secretion, and reduced cytotoxicity. Treatment-free intervals induced transcriptional reprogramming of T cells, maintained high metabolic fitness, and reinvigorated T cell functions. In a PDX model of ALL, treatment-free interval-stimulated T cells showed improved antileukemic efficacy.
Contributed by Shishir Pant
ABSTRACT: T-cell-recruiting bispecific molecule therapy has yielded promising results in patients with hematologic malignancies, however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific molecule blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life-extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; p = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI specific lysis on day 14: 34.9% vs 93.4%; n = 6; p < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.
Author Info: (1) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (2) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (3) Labo
Author Info: (1) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (2) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (3) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (4) German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. (5) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (6) Core Facility Bioinformatics, Biomedical Center, LMU. (7) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (8) LMU Gene center, Munich, Germany. (9) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (10) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (11) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (12) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (13) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (14) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (15) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (16) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (17) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (18) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (19) German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. (20) University Hospital LMU, Munich, Germany. (21) University Hospital, LMU Munich, Munich, Germany. (22) AMGEN Research (Munich) GmbH, Munich, Germany. (23) German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. (24) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany. (25) Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany.
