Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events

Abstract

Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell-independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell-dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) Tcell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. Significance: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.

AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

“…Given the high affinity binding of AMG 757 to NHP DLL3 and CD3, and the potent activity of NHP effector cells in redirected lysis of SCLC tumor cells, the in vivo safety profile strongly suggests that DLL3 expressed on normal tissues is largely inaccessible to AMG 757 target engagement. BiTE ® molecules may access targets expressed in brain, as blinatumomab has been detected in the brain and can be associated with neurologic events, and an EGFRvIII-targeting BiTE ® molecule, AMG 596, is in development for glioblastoma (42)(43)(44).…”

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

“…Due to its high clearance rate, interruption of blinatumomab treatment is sufficient to resolve most neurologic events, although some resulted in treatment discontinuation. While the exact mechanism of CD19-mediated neurotoxicity is unclear, adhesion of T cells to endothelial cells may be involved [47].…”

Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia

“…Subsequently, in a B-cell-dependent phenomenon, blinatumomab promotes T-cell activation and cytokine release, triggering neurotoxicity. 23 …”