Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy

Abstract

Selinexor (KPT-330) is a first in class nuclear transport inhibitor currently in clinical trials as an anti-cancer agent. To determine how selinexor might impact anti-tumor immunity, we analyzed immune homeostasis in mice 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 naïve 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 melanoma, selinexor treatment at 10 mg/kg with a 5 day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable to vehicle treated mice. 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-tumor immunity.

XPO1 target occupancy measurements confirm the selinexor recommended phase 2 dose

“…This duration of occupancy in animals supports the RP2D dosing regimen of 60 mg twice weekly on days 1 and 3. Such dosing regimen maintains steady state levels of drug-target interaction during the first half of each treatment week and washout / clearance of drug in the second half of the week, resulting in cancer cell growth inhibition / death while allowing recovery of normal tissue [ 19 ].…”

“…This finding supports the RP2D dosing regimen, where 10-15 mg/kg in mice (approximately equivalent to 50-75 mg flat dose in humans) is necessary to maintain XPO1 occupancy for up to 48 hours post-dose, thus requiring the twice weekly dosing for continuous target occupancy during the first half of each treatment week and washout / clearance during the second half of the week. The relief of target occupancy during the 5 day drug holiday is necessary for the recovery of normal cells, such as to allow CD8 T cells to launch an effective anti-tumor response [ 19 ], as well as to allow megakaryocyte differentiation to alleviate the main selinexor side effect, thrombocytopenia [ 29 ]. Together, these studies support the 60 mg BIW schedule empirically determined in the clinic [ 8 , 9 , 18 ].…”

High-throughput organoid screening enables engineering of intestinal epithelial composition

“…4A). Given animal weight loss on the standard chemotherapeutic dosage regimen, and additional evidence that sustained dosage of SINEs adversely impacts T cell populations (Tyler et al, 2017), we sought to explore dosing regimens well below 10 mg/kg, to assess if a pro-Paneth phenotype may exist below potential toxicities.…”

Targeting Immunotherapy to the Tumor Microenvironment

“…Several small molecules developed as cancer therapeutics have effects on cells of the immune system. IAP antagonists, BTK inhibitors, adenosine receptor (A2A) antagonists, and SINE compounds are a few examples [Dougan et al, ; Clancy‐Thompson et al, ; Gunderson et al, ; Tyler et al, ]. These agents have broad activity in many immune cell types throughout the body, and thus side effects of treatment may be diminished if the drugs were concentrated in the tumor microenvironment.…”

“…SINE compounds block nuclear export via XPO1, and trap NF‐κB in the nucleus in an inactive form. T cell receptor signaling is completely abrogated in the presence of SINE compounds, although intermittent dosing can mitigate the negative effects of SINE compounds on anti‐tumor T cell responses [Tyler et al, ]. Nevertheless, strategies to target SINE compounds to the tumor microenvironment and spare the draining lymph node, would allow for T cell priming to continue unabated even with more frequent dosing.…”