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• W325028298 abstract "Abstract Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), an aggressive malignancy derived from plasmacytoid dendritic cells (PDCs), typically presents as cutaneous lesions, can also involve lymph nodes and spleen, and invariably terminates in an acute leukemic phase. Its diagnosis is based on this clinical presentation, as well as the unique pathological and immunophenotypic features of a cutaneous PDC neoplasm, with high expression of CD123 (interleukin-3 receptor [IL-3R]), CD304, and/or CD303 (Garnache-Ottou F et al., 2009); CD56 and CD4 are also commonly expressed. There is no accepted standard of care to treat BPDCN and therapeutic strategies have never been prospectively evaluated. Treatment approaches include: symptomatic therapy, intensive multi-agent chemotherapy, and allogenic hematopoietic cell transplantation. Although chemotherapy-naive patients often respond to chemotherapy, most subjects experience recurrent disease shortly thereafter; median overall survival ranges from 9 to 13 months. Since BPDCN cells express high levels of IL-3R, the antitumor effects of SL-401, a novel targeted therapy directed to IL-3R, are being evaluated in preclinical and clinical studies. SL-401, which consists of IL-3 fused to a truncated diphtheria toxin payload, potently inhibits protein synthesis following IL-3R-mediated binding and internalization. Since normal hematopoietic cells express negligible levels of IL-3R, myelosuppression is negligible. To better understand the antitumor effects of SL-401 against BPDCN, the cytotoxicity of SL-401 was assessed in BPDCN patient-derived cell lines (CAL-1 and GEN2.2) and primary BPDCN cells isolated directly from patients (n = 12). Cytotoxicity was measured using flow cytometry (AV/7AAD staining) and an MTT assay after SL-401 treatment for 18 or 48 hours, respectively, as a single agent or compared with a range of cytotoxic agents. We confirmed the robust single agent activity of SL-401 against BPDCN cell lines (Angelot-Delettre F et al., ASH 2011) and found that treatment with SL-401 at concentrations substantially lower than peak concentrations achieved in patients induced a percent decrease in viability of BPDCN cell lines of 92% (62 ± 7% to 5 ± 2%) (n = 9 experiments) and primary BPDCN cells of 80% (50 ± 5% to 10 ± 1%) (n = 12 experiments) (Fig. A and B). Moreover, SL-401 was more effective than 7 out of 8 chemotherapeutic agents tested (Fig. C). SL-401 was also evaluated in a NOD-SCID IL2RγcKO (NSG) BPDCN mouse model. After 2 Gy irradiation, mice were injected with GEN 2.2 cells (1 x 106, IV) and then treated with SL-401 at clinically relevant doses or PBS (IP daily for 5 days) initiated on day 7 post-implantation. The median overall survival (OS) was significantly improved in mice receiving a single cycle of SL-401 compared to untreated controls (53 d vs. 15 d, respectively) (Figs. D and E). These findings provide strong in vitro and in vivo evidence that BPDCN cells are highly sensitive to SL-401. Since BPDCN patients express high levels of IL-3R (Garnache Ottou et al, 2009), these results also indicate that SL-401 may provide a clinical benefit for BPDCN patients. A Phase 2 multi-cycle trial in this orphan indication is currently being planned in North America and Europe. Download : Download high-res image (56KB) Download : Download full-size image Figure. SL-401 is an efficient treatment for BPDCN (A) BPDCN cell lines CAL-1 and GEN 2.2 (n= 9) and (B) primary cells (12 patients) are sensitive to SL-401 (2.7 fM) treatment (18 h) in vitro. **p Disclosures: Frankel: Stemline Therapeutics: Patents & Royalties, Research Funding. Brooks: Stemline Therapeutics: Employment, Equity Ownership. Rowinsky: Stemline Therapeutics: Employment, Equity Ownership." @default.
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• W325028298 date "2013-11-15" @default.
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• W325028298 title "Preclinical Studies Of SL-401, a Targeted Therapy Directed To The Interleukin-3 Receptor (IL3-R), In Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Potent Activity In BPDCN Cell Lines, Primary Tumor, and In An In Vivo Model" @default.
• W325028298 doi "https://doi.org/10.1182/blood.v122.21.3942.3942" @default.
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