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PURPOSE T-cells engineered to express a chimeric antigen receptor (CAR T-cells) are a promising cancer immunotherapy. Such targeted therapies have shown long-term relapse-free survival in patients with B-cell leukemia and lymphoma. However, cytokine release syndrome (CRS) represents a serious, potentially life-threatening side effect often associated with CAR T-cell therapy. CRS manifests as a rapid (hyper)immune reaction driven by excessive inflammatory cytokine release, including interferon-g and interleukin-6. EXPERIMENTAL DESIGN Many cytokines implicated in CRS are known to signal through the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway. Here we study 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. RESULTS We report that itacitinib, a potent, selective JAK1 inhibitor, was able to significantly and dose-dependently reduce levels of multiple cytokines implicated in CRS in several in vitro and in vivo models. Importantly, we also report that at clinically relevant doses that mimic human JAK1 pharmacologic inhibition, itacitinib did not significantly inhibit proliferation or antitumor killing capacity of three different human CAR T-cell constructs (GD2, EGFR, and CD19). Finally, in an in vivo model, antitumor activity of CD19-CAR T-cells adoptively transferred into CD19+ tumor bearing immuno-deficient animals was unabated by oral itacitinib treatment. CONCLUSIONS Together, these data suggest that itacitinib has potential as a prophylactic agent for the prevention of CAR T-cell-induced CRS, and a phase II clinical trial of itacitinib for prevention of CRS induced by CAR T-cell therapy has been initiated (NCT04071366).
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?:doi
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10.1158/1078-0432.ccr-20-1739
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Clinical_cancer_research_:_an_official_journal_of_the_American_Association_for_Cancer_Research
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Itacitinib (INCB039110), a JAK1 inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-Cell Therapy.
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