Abstract
Abstract 2452
CRM1 (chromosomal regional maintenance 1) or XPO1 (exportin 1) is the major protein that mediates nuclear export. XPO1 has been shown to be over-expressed in cancer cells leading to ineffective cytoplasmic localization of multiple tumor suppressor genes such us p53, FOX03a, and Iκ-β. Chronic Lymphocytic Leukemia (CLL) is characterized by disrupted apoptosis caused both by microenviromental stimuli and aberrant activation of survival pathways including PI3K/Akt, NF-kB, and p53. We previously showed that first generations Selective Inhibitor of Nuclear Export (SINE), KPT-185 and KPT-251, specifically bind to and block XPO1 function resulting in re-activation of tumor suppressor pathways and apoptosis in CLL. Furthermore, we showed that KPT-251 at 75mg/Kg, 3 times per week (QODX3) slowed disease progression, and improved overall survival in the Eμ-TCL1-SCID mouse model of CLL (median OS = 130 and 72 days for KPT-330 and vehicle respectively; p=0.01) with minimal weight loss or other toxicities. The goal of this study was to determine the efficacy of KPT-330, a new generation SINE currently in Phase 1 human studies, with improved pharmacokinetic and oral bioavailability, in the Eμ-TCL1-SCID mouse model of CLL. We first compared the in-vitro activity of KPT-330 to KPT-251. KPT-330 induced improved levels of cytotoxicity on CLL cells compared to KPT-251 with retained selective cytotoxicity against tumor cells when compared to peripheral blood mononuclear cells and isolated B, and T cells. Similar to KPT-251, KPT-330 showed enhanced cytotoxic potency on CLL cells under coculture conditions with stromal cells compared to CLL alone (p<0.05). Interestingly KPT-330 prevented CPG induced proliferation of CLL cells (p<0.005) and migration of CLL cells driven by CXCL12 and CXCL13, homing factors for hematopoietic cells to the marrow that are constitutively secreted by bone marrow stromal cells. KPT-330 was also more effective than KPT-251 in mediating cytotoxicity of murine TCL1+ cells in-vitro. We therefore tested the ability of KPT-330 to slow disease progression in Eμ-TCL1-SCID mouse model of CLL in which CD19+ TCL1 leukemia cells were engrafted into SCID mice via tail vein injection. Treatments began 2 weeks post engraftment. 9 or 10 mice in each treatment group were treated with: a) vehicle control twice weekly (BIW), b) KPT-330 5 mg/kg BIW, c) KPT-330 15 mg/kg BIW d) vehicle control QODX3, e) KPT-330 1 mg/kg QODX3 for 9 weeks followed by 15 mg/kg QODX3, f) KPT-330 3 mg/kg QODX3, g) KPT-330 10 mg/kg QODX3 for up to a maximum of 36 weeks. In surviving mice, treatment was stopped after 36 weeks and animals were followed up for 30 additional days. Overall survival (OS) was the primary endpoint. Within the BIW groups, only KPT-330 at 15 mg/kg (median OS = undefined p=0.0002) showed a significant improvement over vehicle (median OS = 98 days) with 100% of the mice still alive at the end of the study (week 40). Within the QODX3 groups, KPT-330 10 and 15 mg/kg QODX3 (median OS = undefined, 213 days respectively) both showed a significant improvement (p<0.0001) over vehicle (median OS = 98.5). No improvement in survival compared to vehicle treated animals was induced by KPT-330 3 mg/kg. KPT-330 was well tolerated in mice, weight loss suggestive of drug toxicity was seen at the beginning of the study only in groups treated with KPT-330 at doses of >10 mg/kg QODX3 but was fully reversed by the end of the study and did not appear to adversely affect the animals. Moreover, KPT-330 at doses of >10 mg/kg BIW and QODX3 significantly prevented an increase in circulating CLL cells compared to vehicle. To further validate KPT-330 in mice with leukemic phase (ie, very high tumor burdens), 20 additional mice were engrafted with CD19+ TCL1 leukemia cells and treatment with vehicle or 15 mg/kg KPT-330 (QoDx3/wk) was initiated 70 days post engraftment. Mice treated with KPT-330 had a significant survival advantage (p=0.0008, median OS = undefined; 99 days, for KPT-330 and vehicle respectively). KPT-330 was strikingly active in prolonging survival of TCL1-SCID mice. Using CLL as a disease model we validate the clinical effectiveness of targeting XPO1 with use of SINE, with favorable therapeutic index in-vivo. These data strongly support the ongoing Phase 1 clinical studies of KPT-330 in patients with advanced hematologic malignancies including CLL.
Disclosures:
Sandanayaka: Karyopharm Therapeutics: Employment. Shechter:Karyopharm Therapeutics: Employment. McCauley:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics Inc: Employment.
Temporary restoration of immune response against Toxoplasma gondii
in HIV-infected individuals after HAART, as studied in the hu-PBMC-SCID mouse model