Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR.
SummaryDespite considerable advances, multiple myeloma (MM) remains incurable and the development of novel therapies targeting the interplay between plasma cells (PCs) and their bone marrow (BM) microenvironment remains essential. We investigated the effect of various agents in vitro on the proliferation, phenotype, morphology, actin polymerization and migration of MM cells and, in vivo, the tumour growth of L363-bearing non-obese diabetic severe combined immunodeficient mice with a deficient interleukin-2 receptor gamma chain (NSG). In vitro, we observed a dose-dependent cytotoxicity with bortezomib and sorafenib. Using RPMI8226 cells co-expressing histone 2B-mCherry and cytochrome c-GFP, bortezomib-and sorafenib-induced apoptosis was confirmed, and both agents combined showed synergism. Sorafenib induced CD138-downregulation and abolished CXCL12-induced actin polymerization. L363 cells expressed CCR4 and CCR5 and migrated to their common ligand CCL5. Chemotaxis to BM stroma cells was notable and significantly reduced by sorafenib. Downregulation of phospho-ERK appeared relevant for the inhibition of actin polymerization and chemotaxis. Sorafenib alone, and combined with bortezomib, showed substantial antitumour activity in L363-bearing NSG. Correspondingly, sorafenib induced clinical responses in MM-/AL-amyloidosis patients. We conclude that, in addition to the cytotoxic and anti-angiogenic effects of sorafenib, blocking of MM cell migration and homing represent promising mechanisms to interrupt the interplay between PCs and their supportive microenvironment.
Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133ÂCD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133þ GBM stem cells (GBM-SC),inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts.Moreover, upon intracerebral infusion along with the local application of human CD8 þ T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC-derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM. Cancer Res; 75(11); 2166-76. Ó2015 AACR.
Engelhardt. Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma). Haematologica. 2018; 103:xxx doi:10.3324/haematol.2018.189969 Publisher's Disclaimer. Vorinostat is an oral class I/II HDACi and has been investigated with bortezomib in a randomized phase III trial for RRMM patients: this VANTAGE088 study reported a median PFS of 7.6 vs. 6.8 months for (Table 1A). The synergism of vorinostat and bortezomib is depicted in Fig.S1A. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.All patients suffered from relapsed (n=23) or RRMM (n=10). The median age was 62 years, which was comparable or more advanced to others (Table 1B). In line with our earlier description of age and stage migration, 8 we here observed more elderly, unfit and advanced MM stages. [8][9][10] The Revised Myeloma Comorbidity Index (R-MCI) was 4, thus patients were by definition intermediate-fit. In line, their Charlson Comorbidity Index (CCI) was 2 vs. 1 in our control patients (Table 1C). For comparison, Palumbo et al.described their elderly clinical trial cohort with a CCI of 0. 11Our pretreatment with PIs, IMiDs and autologous stem cell transplantation (ASCT) was similar to others. 5,12,13 The number of prior lines was 3: virtually all (91%) had received ASCT, bortezomib (88%) and IMiDs (42%). The median bone marrow (BM) infiltration was 40%, iFISH showed HR in 18% and unfavorable cytogenetics (CG) in 52% (Table 1A+B). The VBDD data were presented as of 12/2016 with at least one year follow-up of the last patient being treated. NA being approved in Europe since 2016, 3 such as daratumumab (Dara), elotuzumab, carfilzomib or ixazomib, had not been available for RRMM patients outside clinical trials at that time.14 With three patients having been treated in each dose level (DL) 0 and +1, without any DLT during the first cycle, the remaining 27 proceeded to DL+2. Common hematologic side effects (AEs) included anemia and thrombocytopenia. Non-hematological AEs included infections, amongst others three cases of sepsis, three with pneumonia, and one each with esophageal candidiasis, colitis and herpes zoster reactivation.Others included one case of syncope and cerebral seizure in a patient with seizure history (Table 2).Cardiotoxicity was not observ...
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