AUTHOR=Vicenova Paulina , Maher John 
  
TITLE=How can we balance risk and benefit of interleukin-18 armored T cell therapies?
  
JOURNAL=Experimental Biology and Medicine
  
VOLUME=Volume 251 - 2026
  
YEAR=2026
  
URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2026.10938
  
DOI=10.3389/ebm.2026.10938
  
ISSN=1535-3699
  
ABSTRACT=CD19-specific CAR T cells engineered to secrete a constitutively active form of the pro-inflammatory cytokine, interleukin (IL)-18 have demonstrated impressive efficacy in a recent clinical trial involving subjects who had failed prior CAR T cell therapy. Corroborating these clinical data, preclinical studies of IL-18-armored CAR and T cell receptor-engineered T cells have demonstrated enhanced anti-tumor activity in several xenograft and syngeneic mouse cancer models. Interleukin-18 improves tumor clearance via direct effects on CAR T cells and indirect actions on cells on a variety of host immune cells, including natural killer, macrophage and dendritic cells. Compared to unarmored CAR T cells, IL-18-secreting CAR T cells are less exhausted, expand more efficiently and produce greater quantities of interferon (IFN)-γ. However, upregulated circulating IL-18 and its downstream mediator, IFN-γ, are also associated with systemic toxicities which have proven to be severe on occasions. In light of this, several groups have developed strategies that set out to restrict IL-18 release or biological activity to the tumor microenvironment. Among these, CAR T cells armored with NFAT-inducible IL-18 are now undergoing clinical testing. The evaluation of inducible or tumor-selective IL-18 deployment will show whether it is possible to minimize IL-18 related systemic toxicities while preserving localized amplification of anti-tumor activity.