2ⁿᵈ Edition of the Cancer R&D World Conference 2026

T cell engager (TCE) therapies represent an established class of cancer immunotherapies that redirect endogenous T cells toward tumor cells through binding to tumor-associated antigen(s) and CD3. This induced proximity and T-cell receptor clustering causes T cell activation and tumor cell killing. Despite showing clinical efficacy, TCE therapies are frequently associated with immune-related toxicity.

TCE-activated T cells release pro-inflammatory cytokines which can activate other immune cells, especially monocytes and macrophages, and amplify inflammatory signaling through mediators such as GM-CSF, IL-1β, and IL-6. This cytokine cascade underlies cytokine release syndrome (CRS), the severity of which correlates with immune-effector cell-associated neurotoxicity syndrome (ICANS). Furthermore, emerging clinical and translational evidence suggests that endothelial activation and blood brain barrier (BBB) disruption contribute to ICANS pathophysiology. Better preclinical models are needed to predict TCE-associated ICANS and BBB disruption.

Existing in vitro BBB models used to evaluate cytokine-mediated neurotoxicity are often limited to brain microvascular endothelial cells (BMECs) and lack other key neurovascular components such as pericytes and astrocytes, which are critical for BBB integrity. In vivo models (i.e., mouse and nonhuman primate) provide additional context but have limited translational relevance due to interspecies differences in CNS physiology, immune responses, species cross-reactivity and biomarker expression.

Here, we aimed to assess TCE-associated immunotoxicity and neurovascular injury using a multicellular human BBB model designed to recapitulate key features of BBB structure and function.

We leveraged a commercially available multicellular BBB model, comprised of three essential human BBB cell types: BMECs, astrocytes, and pericytes. This configuration supports BMEC maturation and formation of a physiologically relevant barrier with transendothelial electrical resistance (TEER) values of ~4,000–5,000 Ω·cm², exceeding many previously reported in vitro models, which typically remain below commonly cited physiological thresholds (>1,500 Ω·cm²).