Mosunetuzumab is a T-cell reliant bispecific antibody that binds to CD3 and CD20 to trigger T-cell mediated B-cell death.
However, cytokine release syndrome, which has the potential to limit dose and efficacy, can result from powerful immune stimulation with T-cell focused treatments.
We created a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), taking into account the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumors, in order to better understand the mechanisms underlying safety and efficacy as well as to explore safety mitigation strategies.
Using mosunetuzumab nonclinical and blinatumomab clinical data, the model was created and validated. The initial step-fractionated dose was projected to minimize systemic T-cell activation and cytokine release without impairing tumour response.
Simulations described the mechanisms underlying the observed cell and cytokine (IL6) dynamics. The Phase I clinical study for mosunetuzumab was changed to a step-fractionated treatment schedule as a result of these findings, allowing for the safer administration of greater dosages.
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