Clinical Pharmacology of Cytokine Release Syndrome with T-Cell-Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies

Abstract

Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell-engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention are crucial in T-BiSp development. Required hospitalization for seven of the nine approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce health care burden and improve patient outcomes. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre) treatment strategies, quantitative pharmacology tools used during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through a review of T-BiSp licensing applications and emerging data from conferences and publications.

Figure 1.

Comparison of CRS across approved T-BiSp. A, Balance of efficacy vs. CRS. Molecule name (target) shown on the left axis and therapeutic indication on the right grouped axis. ORR was used as the efficacy endpoint for comparison across molecules. However, the primary endpoint was overall survival for tebentafusp and blinatumomab. The in-figure text values represent the number of patients contributing to CRS and efficacy assessments provided in the biologics licensing applications. B, CRS event rate per dose period (points, line) overlaid with dose amount (bars) for SUDs and target doses. Dose amounts in milligrams are depicted at scale, except that blinatumomab and tebentafusp are shown in micrograms. B-ALL, B precursor acute lymphoblastic leukemia; BCMA, B-cell maturation antigen; ci.v., continuous intravenous; DLBCL, diffuse large B-cell lymphoma; ES-SCLC, extensive-stage small cell lung cancer; FL, follicular lymphoma; MM, multiple myeloma; mUM, metastatic uveal melanoma; R/R, relapsed or refractory. Note: The unit for blinatumomab dose is micrograms.

Figure 2.

Cytokine dynamics in approved T-BiSp. A, Cytokine biomarkers measured and reported in the nonclinical and clinical pharmacology sections of biological licensing applications (BLA). B, Mean cytokine peaks (lines), as fold change from baseline, overlaid with CRS rates (bars) postdose during the SUD phase. Cytokine levels were digitized from figures in molecule BLAs. Molecules that reported raw cytokine levels were converted to fold change using the mean baseline value. Open circles shown in epcoritamab and tebentafusp panels indicate when only predose cytokine levels were reported. i.v., intravenous; PD, pharmacodynamics (i.e., time-course profiles); s.c., subcutaneous.