ASH 2025: A Newly Identified Role for IL-5 in Regulating CAR T-associated Toxicity and Efficacy

Chimeric antigen receptor (CAR) T-cell therapies have emerged as an important component of the treatment arsenal for B-cell malignancies. Their use, however, has been complicated by a high rate of serious and potentially life-threatening toxicities, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Investigators therefore sought to understand the mechanisms that lead to the development of these toxicities and potential mechanisms to interrupt these processes.

To start with, the team analyzed cytokine levels within the plasma of patients who had recently received CD19-directed CAR T-cell therapy (CART19) for relapsed/refractory large B-cell lymphoma (LBCL) or relapsed/refractory follicular lymphoma (FL). Among this group, 88% developed CRS and 16% developed ICANS. Within the first 30 days after treatment, the investigators found that IL-5 was one of the most highly enriched cytokines, with 6.6-fold increase from Day 0 to peak in people who experienced CRS and an 11.9-fold increase in those who experienced ICANS.

Using a mouse model of B-acute lymphoblastic leukemia (B-ALL), researchers then examined the effect of IL-5 inhibition in animals treated with CART19. They found that the mice treated with an IL-5 inhibitor had reduced weight loss, improved neuroscores, and reduced expression of CRS-associated cytokines compared with mice who received a control treatment. They also found that while all CAR19-treated mice were able to clear the tumor burden, those who received an IL-5 inhibitor had longer overall survival than those who did not.

To further explore the impact of IL-5 on survival outcomes, the researchers knocked out IL-5 or the IL-5 receptor in CART19 cells before infusing them into mice. They found that the knockout mice had improved antitumor activity and improved survival relative to those who still expressed IL-5 or its receptor.

While more research is needed to understand the impact of IL-5 inhibition on CAR T-cell treatment outcomes in patients, the investigators suggested that this may be a promising strategy to improve both efficacy and safety of CAR T-cell therapy for patients with lymphoma.

This research was presented by Foundation Postdoctoral Fellowship grantee Alberto Carturan, MD of the University of Pennsylvania.

This study also included contributions from Foundation grantee Marco Ruella, MD of Perelman School of Medicine at the University of Pennsylvania.