sepantronium and Multiple-Myeloma

Topics: Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Bone Marrow Cells; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Immunotherapy; Multiple Myeloma; Naphthoquinones; Stromal Cells; T-Lymphocytes, Cytotoxic

The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.

Topics: Antineoplastic Agents; Apoptosis; Cell Growth Processes; Cell Line, Tumor; Cohort Studies; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Interleukin-6; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Naphthoquinones; Prognosis; STAT3 Transcription Factor; Survival Analysis; Survivin; Transcriptome; Unfolded Protein Response

Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.. Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.. Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.. These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

Topics: Animals; Antineoplastic Agents; Cell Adhesion; Cell Communication; Cell Line, Tumor; Combined Modality Therapy; Cytotoxicity, Immunologic; Disease Models, Animal; fas Receptor; Humans; Imidazoles; Immunomodulation; Immunotherapy, Adoptive; Mice; Multiple Myeloma; Naphthoquinones; T-Lymphocytes, Cytotoxic; Tumor Microenvironment; Xenograft Model Antitumor Assays