Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy.
Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor 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 culturedin vitroshowed 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 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ+, granzyme B+cytotoxic CD8 T cells that were comparable with 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 antitumor immunity.Mol Cancer Ther; 16(3); 428-39. ©2017 AACRSee related article by Farren et al., p. 417.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Paul M
PM
Tyler
Dana-Farber Cancer Institute, Boston, Massachusetts.
Mariah M
MM
Servos
Dana-Farber Cancer Institute, Boston, Massachusetts.|University of Amsterdam, Program in Biomedical Sciences, Amsterdam, the Netherlands.
Romy C
RC
de Vries
Karyopharm Therapeutics, Inc., Newton, Massachusetts.
Boris
B
Klebanov
Karyopharm Therapeutics, Inc., Newton, Massachusetts.
Trinayan
T
Kashyap
Karyopharm Therapeutics, Inc., Newton, Massachusetts.
Sharon
S
Sacham
Karyopharm Therapeutics, Inc., Newton, Massachusetts.
Yosef
Y
Landesman
Massachusetts General Hospital, Boston, Massachusetts.
Michael
M
Dougan
Dana-Farber Cancer Institute, Boston, Massachusetts. Stephanie_Dougan@dfci.harvard.edu.
Stephanie K
SK
Dougan
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D007109:Immunity / Q000187:drug effects*; D056747:Immunomodulation / Q000187:drug effects; D007167:Immunotherapy; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D015415:Biomarkers; D006834:Hydrazines; D011948:Receptors, Antigen, T-Cell; D014230:Triazoles; C585161:selinexor