Itacitinib, a selective JAK1 inhibitor, may be a potential prophylactic agent for the prevention of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome (CRS), according to a study published in Clinical Cancer Research.
CRS is a serious, potentially life-threatening adverse event often associated with CAR T-cell therapy. It manifests as a rapid hyperimmune reaction driven by excessive inflammatory cytokine release, including interferon-g and interleukin-6. Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Researchers assessed the effect of blocking JAK pathway signaling on CAR T-cell proliferation, anti-tumor activity, and cytokine levels in in vitro and in vivo models.
The study found that itacitinib significantly and dose-dependently reduced levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. In addition, at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or anti-tumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19).
In an in vivo model, anti-tumor activity of CD19 CAR T-cells adoptively transferred into CD19+ tumor bearing immunodeficient animals was unabated by oral itacitinib treatment.
The researchers noted that based on the findings, a phase II clinical trial of itacitinib for the prevention of CAR T-cell therapy-related CRS has been initiated.