Patients with hematologic malignancies have had encouraging outcomes using T-cell-recruiting bispecific molecule treatment, although resistance and subsequent recurrence remain significant obstacles. In addition, results of T-cell-based immunotherapies have been shown to be compromised by T-cell fatigue brought on by prolonged antigen stimulation or tonic receptor activation. But nothing was known about how repeated exposure to bispecifics affected T-cell performance.

Patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia experienced decreased T-cell activity after receiving blinatumomab, a bispecific CD19xCD3 molecule, for 28 days. With the help of an in vitro model system that replicated a continuous 28-day infusion of the CD19xCD3 bispecific AMG 562, researchers could spot telltale signs of depletion as they developed over time.

Progressive loss of T-cell function was brought on by ongoing exposure to AMG 562 (mean specific lysis on days 7 and 28 was 88.4% vs. 8.6%; n=6; P=.0003). AMG 562 discontinuation was found to be a highly effective method for achieving treatment-free intervals (TFIs), which are a potent method for preventing tiredness. TFIs produced strong functional reinvigoration and transcriptional reprogramming in T cells (continuous versus TFI-specific lysis on day 14: 34.9% vs. 93.4%; n = 6; P<.0001). Additionally, the addition of a TFI increased in vivo tumor suppression and T-cell growth. The findings underscored the importance of T-cell fatigue in bispecific antibody treatment and the potential of TFIs to revive T cells both transcriptionally and functionally.

The findings highlighted the necessity to consider and assess TFIs in application schedules to optimize clinical outcomes, especially given the expanding number of bispecific compounds investigated in clinical trials.