Purpose: T cells engineered to express a chimeric antigen receptor (CAR) 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 IFNγ and IL6. 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).

Type 1 diabetes mellitus (T1D) is an autoimmune illness that affects millions of patients worldwide. The main characteristic of this disease is the destruction of pancreatic insulin-producing beta cells that occurs due to the aberrant activation of different immune effector cells. Currently, T1D is treated by lifelong administration of novel versions of insulin that have been developed recently; however, new approaches that could address the underlying mechanisms responsible for beta cell destruction have been extensively investigated. The strategies based on immunotherapies have recently been incorporated into a panel of existing treatments for T1D, in order to block T-cell responses against beta cell antigens that are very common during the onset and development of T1D. However, a complete preservation of beta cell mass as well as insulin independency is still elusive. As a result, there is no existing T1D targeted immunotherapy able to replace standard insulin administration. Presently, a number of novel therapy strategies are pursuing the goals of beta cell protection and normoglycemia. In the present review we explore the current state of immunotherapy in T1D by highlighting the most important studies in this field, and envision novel strategies that could be used to treat T1D in the future.

Chimeric antigen receptor (CAR) T‐cell therapy against tumor antigens involves a recombinant immunoreceptor that combines an antibody‐derived targeting fragment with signaling domains capable of activating T cells and fusion of this receptor domain to a costimulatory domain (typically CD28 or 4‐1BB). Clinical trials of CAR T‐cell therapeutics targeting CD19 antigens for relapsed or refractory B‐cell malignancies have shown unparalleled results and consequently have recently been approved by the U.S. Food and Drug Administration. However, the lack of efficacy beyond B‐cell malignancies, the emergence of resistance to CAR T‐cell therapy due to loss of the antigenic epitope, and severe cases of cytokine release syndrome and neurotoxicity necessitate further preclinical studies. As it is very complicated to develop a single animal model that would replicate the complexity of the clinical scenario, this article focuses on transgenic models used to study human tumor‐associated antigens in an immunocompetent model. © 2019 by John Wiley & Sons, Inc.

Allergic contact dermatitis is driven by an overreaction of the body's immune system to a normally harmless substance resulting in skin inflammat |