SL-401, A Novel Targeted Therapy Directed To The Interleukin-3 Receptor (IL-3R), Inhibits Plasmacytoid Dendritic Cell (pDC)-Induced Myeloma Cell Growth and Overcomes Drug Resistance

Abstract

IntroductionMultiple Myeloma (MM) remains incurable despite the advent of novel drugs, highlighting the need for further identification of factors mediating disease progression and resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our earlier study using both in vitro and in vivo MM xenograft models showed increased numbers of plasmacytoid dendritic cells (pDCs) in the MM BM, which promote MM cell growth and survival (Chauhan et al., Cancer Cell 2009, 16:309-323). We found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDC survival. Interestingly, the IL-3 receptor (IL-3R) is highly expressed on pDCs. In this study, we utilized SL-401, a novel targeted therapy directed to IL-3R, to examine whether blockade of the IL-3-IL3R signaling axis inhibits pDC-induced MM cell growth. MethodsTo study the anti-MM activity of SL-401, we utilized MM cell lines, patient MM cells, and pDCs from normal healthy donors or MM patients. The pDCs and MM cells were cultured alone or together in the presence or absence of SL-401, and cell growth or viability was analyzed using WST/MTT assays. ResultsMM cells or pDCs were freshly isolated and treated with various concentrations of SL-401. SL-401 significantly decreased the viability of pDCs even at low concentrations (IC50: 0.83 ng/ml; 14.6 pM) (mean ± SD; n=4, P < 0.005). SL-401 decreased the viability of MM cells at clinically achievable doses, without significantly affecting the viability of normal peripheral blood mononuclear cells. Co-culture of pDCs with MM cells triggered growth of various MM cell lines, which was blocked in the presence of low concentrations of SL-401 (0.8 ng/ml). MM patient-derived pDCs also induced proliferation of MM cell lines and primary MM cells; and importantly, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005). Moreover, 3 of 5 samples were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, SL-401 blocked pDC-induced growth of dexamethasone-, doxorubicin- or melphalan-resistant MM cell lines (MM.1R, Dox-40 and LR5 cell lines, respectively). Finally, combinations of SL-401 with bortezomib, melphalan, or lenalidomide showed synergistic anti-MM activity. ConclusionsOur preclinical study provides the basis for directly targeting pDCs and inhibiting the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies using SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome. Disclosures:Macri:Stemline Therapeutics, Inc., New York, NY USA : Employment. Brooks:Stemline Therapeutics, Inc., New York, NY USA : Employment. Rowinsky:Stemline Therapeutics, Inc., New York, NY USA : Employment.