UNASSIGNED: Selinexor ( @entity32392 ) is a first in class nuclear transport inhibitor currently in clinical trials as an anti- @entity5 agent. To determine how selinexor might impact anti- @entity5 immunity, we analyzed immune homeostasis in @entity19 treated with selinexor and found disruptions in T cell development, a progressive loss of CD8 T cells and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both na  ve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T cell development and function. We determined the minimum concentration of selinexor required to block T cell activation, and showed that T cell inhibitory effects of selinexor occur at levels above 100nM, corresponding to the first 24 hours post-oral dosing. In a model of implantable @entity320 , selinexor treatment at 10 mg/kg with a 5 day drug holiday led to intratumoral IFNy+, granzyme B+ cytotoxic CD8 T cells that were comparable to vehicle treated @entity19 . Overall, selinexor treatment leads to transient inhibition of T cell activation but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T cell functioning and development of anti- @entity5 immunity.

Clinical dosing regimen of selinexor maintains normal immune homeostasis and T cell effector function in XXXX : implications for combination with immunotherapy.

@entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'cancer'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma'] @entity32392 :: ('MESH:C585161', 'Chemical') :: ['KPT-330']
@entity19 :: (10090,Species) :: ['mice']
