Abstract | PURPOSE: EXPERIMENTAL DESIGN: Many cytokines implicated in CRS are known to signal through the JAK-STAT pathway. Here we study the effect of blocking JAK pathway signaling on CAR T-cell proliferation, antitumor 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 immunodeficient 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).
|
Authors | Eduardo Huarte, Roddy S O'Connor, Michael T Peel, Selene Nunez-Cruz, John Leferovich, Ashish Juvekar, Yan-Ou Yang, Lisa Truong, Taisheng Huang, Ahmad Naim, Michael C Milone, Paul A Smith |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 26
Issue 23
Pg. 6299-6309
(12 01 2020)
ISSN: 1557-3265 [Electronic] United States |
PMID | 32998963
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Copyright | ©2020 American Association for Cancer Research. |
Chemical References |
- Azetidines
- Cytokines
- INCB039110
- Isonicotinic Acids
- JAK1 protein, human
- Janus Kinase 1
|
Topics |
- Animals
- Apoptosis
- Azetidines
(pharmacology)
- Cell Proliferation
- Cytokine Release Syndrome
(drug therapy, etiology, pathology)
- Cytokines
(antagonists & inhibitors)
- Female
- Humans
- Immunotherapy, Adoptive
(adverse effects)
- Isonicotinic Acids
(pharmacology)
- Janus Kinase 1
(antagonists & inhibitors)
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, SCID
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
(drug therapy, immunology, pathology)
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
|