Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling

Abstract

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of Band T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.

Bench‐to‐bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic‐pharmacodynamic model: A case study with anti‐BCMA CAR‐T

“…This integrated PK-PD framework to describe the cellular kinetics of CAR-T cells could be leveraged in the future to characterize the two commonly observed toxicities with CAR-T cell therapies, i.e. cytokine release syndrome (CRS)40 and immune effector cellassociated neurological syndrome (ICANS) 41, 42 . Currently the complexity of the model structure is limited by the availability of clinical datasets.…”

Quantitative Clinical Pharmacology of T‐Cell Engaging Bispecifics: Current Perspectives and Opportunities

“…This temporal pattern associated with CRS offers an opportunity to dissociate the drivers for safety from efficacy to broaden the therapeutic window of TDBs. Specifically, through QSP and E‐R modeling of IL‐6 and CRS events, implementation of step‐up dosing, in which small but pharmacologically active doses associated with low CRS risk, are initially administered to reduce circulating target cells and/or invoke immune desensitization 35 . Thereafter, high therapeutic doses are administered to achieve efficacy within the plateau of response; thus, enabling a QCP informed dosing approach for TDBs ( Figure ).…”

“…Hosseini et al . introduced a QSP model that explicitly includes blood and lymphoid tissues, and trafficking of CD8 + T lymphocytes and target cells between these tissues; uses in vivo preclinical and clinical PK/PD data for model calibration and validation; and describes both safety (cytokines) and efficacy (target cell depletion) aspects of treatments with TDBs 35 . Notably, the key factors for the successful application of QSP modeling, in this case, to inform the clinical development of mosunetuzumab, included: (1) the ability to establish the preclinical‐to‐clinical translation of the dynamics of immune cells (i.e., T and B cells) and IL‐6 response, (2) the availability of a surrogate PD biomarker of IL‐6 for inferences of clinical safety, and (3) the ability to foster a healthy learn‐and‐confirm cycle by incorporating key elements of model‐informed dosing hypothesis in the design of phase I clinical dose finding.…”

“…Notably, the key factors for the successful application of QSP modeling, in this case, to inform the clinical development of mosunetuzumab, included: (1) the ability to establish the preclinical‐to‐clinical translation of the dynamics of immune cells (i.e., T and B cells) and IL‐6 response, (2) the availability of a surrogate PD biomarker of IL‐6 for inferences of clinical safety, and (3) the ability to foster a healthy learn‐and‐confirm cycle by incorporating key elements of model‐informed dosing hypothesis in the design of phase I clinical dose finding. This approach was used to inform the step‐up clinical dosing strategy used for mosunetuzumab and is being investigated for glofitamab 12,13,35 . Recently, Jiang et al .…”

An autologous culture model of nodal B-cell lymphoma identifies ex vivo determinants of response to bispecific antibodies

“…Despite an overall response rate of up to 69 % in relapsed and refractory B-NHL patients, blinatumomab has never been approved for any B-NHL entity [10][11][12] . Recently, several anti-CD20 BsAb have demonstrated promising preclinical activity [13][14][15][16] and are currently under investigation as single or combination agents in patients with relapsed and refractory B-NHL (e.g. NCT03677154, NCT03671018, NCT04246086, NCT04313608).…”