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NEOPLASIA
From the Jerome Lipper Multiple Myeloma Center,
Department of Adult Oncology, Dana-Farber Cancer Institute, and the
Department of Medicine, Harvard Medical School, Boston, MA; the Celgene
Corporation, Warren, NJ; and the University of Leeds, United
Kingdom.
The antiangiogenic activity of thalidomide (Thal), coupled with an
increase in bone marrow angiogenesis in multiple myeloma (MM), provided
the rationale for the use of Thal in MM. Previously, the direct anti-MM
activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on
MM cells was demonstrated, suggesting multiple mechanisms of action. In
this study, the potential immunomodulatory effects of Thal/IMiDs in MM
were examined. It was demonstrated that Thal/IMiDs do not induce T-cell
proliferation alone but act as costimulators to trigger proliferation
of anti-CD3-stimulated T cells from patients with MM, accompanied by
an increase in interferon- Recent reports of increased bone marrow
angiogenesis in multiple myeloma (MM), coupled with the known
antiangiogenic properties of thalidomide (Thal), provided the rationale
for its use to treat patients with MM. Remarkably, Thal produced
clinical responses in 32% of patients whose disease was refractory to
conventional and high-dose therapy.1 However, there was no
correlation of bone marrow angiogenesis with response to treatment,
suggesting that Thal may not mediate its anti-MM activity through its
antiangiogenic effects alone. We have previously demonstrated that Thal
and 3 immunomodulatory drugs (IMiDs), potent Thal analogues, can act directly on MM cells.2 These drugs induce a dose-dependent inhibition of proliferation even in MM cell lines and patient MM cells
resistant to conventional chemotherapy, and they add to the effect of
dexamethasone (Dex). Thal and IMiDs induce growth arrest or apoptosis,
and, as with Dex, apoptosis is mediated by the activation of related
adhesion focal tyrosine kinase (RAFTK).2,3 For Thal, these
effects were observed only at relatively high concentrations not
readily achievable in plasma, suggesting that there may be alternative
mechanisms for its clinical anti-MM activity.
For many years the immunomodulatory effects of Thal have provided the
rationale for its use in the treatment of a broad range of diseases,
including erythema nodosum leprosum, aphthous ulceration complicating
human immunodeficiency virus, and graft-versus-host disease.4-6 Its mechanism of action was initially thought
to be through the inhibition of cytokine production by monocytes, particularly tumor necrosis factor In this study, we have investigated the immunomodulatory effects of
Thal and 3 potent IMiDs in MM. Although these drugs induce the
proliferation of MM patient T cells as well as IFN- Tumor-derived cell lines and MM patient cells HS Sultan, Raji,
and K562 cell lines were obtained from American Type Culture Collection
(Rockville, MD). MM.1S cells were a kind gift from Dr Steven Rosen
(Northwestern University, Chicago, IL). Cells were cultured in
RPMI-1640 media (Sigma Chemical, St Louis, MO) containing 10% fetal
bovine serum, 2 mM L-glutamine (Gibco, Grand Island, NY), 100 U/mL
penicillin, and 100 µg/mL streptomycin (Gibco). PBMCs were obtained
from normal donors and MM patients (1 newly diagnosed, 2 receiving
induction chemotherapy, 1 after autologous transplantation, and 2 receiving therapy for relapsed disease) after written informed consent
according to institutional guidelines. No patient had received previous
thalidomide or antiangiogenic therapy. Mononuclear cells were isolated
by centrifugation on Ficoll-Paque (Pharmacia Biotech, Piscataway, NJ),
and cells were cultured in RPMI-1640 media supplemented with 10% human
serum. Patient MM cells, greater than 90%
CD38+CD45 Preparation of Thal and IMiDs
T-cell proliferation assays
Generation of CTL and lines with increased NK-cell activity CTL lines were generated by culturing PBMCs from MM patients (1 × 107) with dendritic cells at a ratio of 40:1. After the first 48 hours of culture, IL-2 (20 U/mL; Collaborative Biomedical Products, Bedford, MA) was added. Cells were treated with Thal/IMiD (1 and 5 µg/mL) on alternate days, and standard chromium 51 Cr (51Cr) release assays were performed on days 10 to 14. Lines with increased NK-cell activity were generated by first depleting monocytes from PBMCs by adherence for 2 hours. Nonadherent cells were cultured with IL-2 (10 U/mL) for 72 hours, and this was followed by the daily addition of Thal or IMiDs for 72 hours. 51Cr release assays and flow cytometric analysis were performed at 144 hours.Cytotoxicity assays Effector cells generated as described above were tested for their MM-specific cytotoxicity in a standard 4-hour 51Cr-release assay. Briefly, 1 × 106 target cells were labeled with 100 µCi 51Cr (New England Nuclear) for 60 minutes at 37°C and were washed 3 times to remove unincorporated isotope. Labeled targets were added to 96-well U-bottom plates (1 × 104 cells/well) and incubated with varying ratios of effector cells for 4 hours at 37°C in a 5% CO2 atmosphere. Supernatants were assayed for 51Cr release in a gamma counter. Spontaneous release of 51Cr was assessed by the incubation of targets in the absence of effectors, and maximum release of 51Cr was determined by incubation of targets in 0.1% Triton X-100. Percentage of specific 51Cr release was determined using the following equation: [% specific lysis = (experimental release spontaneous release)/(maximum release spontaneous release) × 100]. Assays were performed in triplicate, and results were expressed as mean ± SD.
MM.1S and HS Sultan cell lines were chosen as targets because they were relatively resistant to NK-cell-mediated lysis; in all experiments, K562 was used as a positive control. To confirm whether the CTLs were class I- or class II-restricted, anti-MHC class I and class II blocking antibodies were added to the target at a concentration of 20 µg/mL and were incubated for 60 minutes on ice before 51Cr release assay. To confirm whether cytotoxicity was NK-cell-mediated, either CD4+, CD8+, CD14+, or CD56+ cells were depleted (more than 97% depletion by flow cytometry) from PBMCs using immunomagnetic beads (Dynal, Lake Success, NY.) immediately before 51Cr release assay. Cold target inhibition assays were performed using the NK-sensitive, LAK-sensitive cell line K562 and the NK-resistant, LAK-sensitive cell line Raji. Effectors were derived from normal PBMCs as described above. Unlabeled competitor targets (Raji) were added in varying ratios to labeled targets (K562) at a standard 30:1 effector-target ratio, and percentage lysis was determined as described above. To control for possible adverse effects of the DMSO vehicle, medium alone was also used as a negative control in all experiments. In all cases, DMSO and media-alone cultures were equivalent. All cell line experiments were repeated at least 3 times. Flow cytometry analysis Flow cytometry analysis was performed using the Coulter Epics XL (Coulter, Miami, FL) to determine the expression of T-cell antigens (CD3, CD4, CD8), NK-cell antigen (CD56), and NK-cell-activation antigens (CD2, CD11a, CD31, CD69, HLA DR; (Beckman Coulter). Cells were washed and incubated in phosphate-buffered saline with 20% human AB serum at room temperature for 20 minutes to eliminate nonspecific Fc receptor binding. Afterward, cells were incubated with murine antibodies directly labeled with either FITC or PE for 30 minutes on ice. Cells were then washed, fixed with 2% paraformaldehyde, and evaluated by flow cytometry.In vivo effect of Thal therapy Patients were treated with 200 to 800 mg/day Thal according to an institutional protocol. Phenotypic analysis of T-cell subsets in the peripheral blood was performed every 4 weeks during Thal therapy.Cytokines Tissue culture supernatants were harvested and frozen immediately at80°C. Assays were performed in triplicate for
IFN- and IL-2 using enzyme-linked immunosorbent assays (R&D Systems).
Statistical analysis Statistical significance of differences observed in drug-treated versus control cultures was determined using the Student t test. The minimal level of significance was P < .05.
Effect of Thal and IMiDs on T cells in healthy donors and patients with MM As in previous reports,8 we found no proliferation of CD3+ cells triggered by treatment with Thal or IMiDs alone (data not shown). However, Thal induced an increased proliferation (mean stimulation index, 3.2; range, 1.5-5.9) of CD3+ cells from healthy donors and patients with MM, cultured either in the presence of anti-CD3 or dendritic cells. Treatment with IMiDs 1, 2, and 3 triggered greater increments in proliferation of CD3+ cells in healthy donors and patients (IMiD1 mean stimulation index, 3.9; range, 1.3-6.1; IMiD2 mean stimulation index, 6.3; range, 2.5-11.3; IMiD3 mean stimulation index, 3.5; range, 1.3-5.4) (Figure 1A). Stimulation was maximal at 1 to 5 µg/mL, levels readily achievable in plasma; at doses greater than 10 µg/mL, a reduction in the fold increase in proliferation was noted (data not shown). In healthy donors and patients with MM, there were interindividual differences in the proliferative response; although the numbers in each group were small, there was no statistical difference between the response of MM patients and healthy donors and no difference between the response of newly diagnosed patients and heavily pretreated patients (Table 1). This drug-induced increase in CD3+ cell proliferation was accompanied by IFN- and IL-2 secretion. As can be seen in Figure 1B,
the increase in cytokine secretion was significantly higher in Thal-
and IMiD-treated cultures than in DMSO-treated controls (Thal,
P = .03; IMiD1, IMiD2, IMiD3, P < .001).
To determine whether the proliferative response was in all T cells or a subset of T cells, we next examined the effect of these drugs on the proliferation of CD3+, CD4+, and CD8+ T cells from 2 patients with MM and 2 healthy donors. As can be seen in Figure 1C, the proliferation of CD4+ (mean stimulation index, 2.6; range, 1.1-4.4) and CD8+ (mean stimulation index, 1.5; range, 0.8-2.2) T-cell subsets was induced by Thal (P = .24). A similar response in CD4+ (mean stimulation index, 2.4; range, 0.5-3.6) and CD8+ (mean stimulation index, 6.4; range, 3.0-11.4) T-cell subsets was triggered by IMiD2 (P = .22). To determine the functional significance of this drug-induced CD3+ cell proliferation in patients with MM, PBMCs treated with Thal/IMiDs for 10 to 14 days were used as effectors and autologous MM cell were used as targets in a standard chromium release assay. Autologous dendritic cells, rather than anti-CD3 antibody, were used to provide a physiological stimulus to trigger through the T-cell receptor. In 2 patients tested, we were unable to demonstrate increased autologous MM cell killing after drug treatment, though control K562 cells were lysed. Flow cytometry analysis of the CTL lines demonstrated a mixed population of T cells (data not shown). Treatment of PBMCs with Thal and IMiDs increases lysis of MM cell lines Given the lack of effect of Thal and IMiDs on CTL activity, we next examined the effect of these drugs on NK- and LAK-cell activity. MM.1S and HS Sultan MM cell lines were chosen as targets because they are relatively resistant to NK/LAK cell lysis and initial experiments demonstrated a 20% difference in MM cell lysis between normal PBMCs stimulated for 72 hours with IL-2 (10 U) and maximal lysis with normal PBMCs stimulated for 72 hours with IL-2 (100 U) (data not shown). Normal PBMCs were treated with IL-2 for 72 hours and then with IL-2 and Thal/IMiDs for 72 hours at a dose of 1 µg/mL. Thal triggered increased MM cell lysis (15.4%) compared to DMSO-treated control (8.4%; P = .07). This increase in MM cell lysis was more marked after treatment with IMiDs (DMSO control, 8.4%; IMiD1, 18.6%, P < .001; IMiD2, 18.2%, P = <.001; IMiD3, 16.5%, P = .02) (Figure 2A). The increase in lysis was also dose dependent: DMSO control, 8.4%; Thal 1 µg/mL, 15.4%, P = .07; Thal 5 µg/mL, 26.2%, P = .004; IMiD1 1 µg/mL, 18.6%, P < .001; IMiD1 5µg/mL, 29.5%, P < .001 (Figure 2B). Next, we determined whether the addition of exogenous IL-2 was essential to observe the drug-induced increase in MM cell lysis. As can be seen in Figure 2C, PBMCs cultured without IL-2 showed less lysis of MM cells, though PBMCs treated with IMiD1 still triggered an increase in MM cell lysis compared to control-treated PBMCs (DMSO control, 3.8%; Thal 5 µg/mL 3.4%; IMiD1 5 µg/mL, 22.2%; P < .001).
Increased MM cell lysis induced by treatment of PBMCs with Thal and IMiDs is NK-cell mediated To determine whether the enhanced MM cell lysis triggered by Thal and IMiDs was mediated by LAK cells or NK cells, cold-target inhibition assays were performed. K562 cells were used as hot targets because they are both NK sensitive and LAK sensitive, and Raji cells were used as the competitive cold target because they are LAK sensitive but NK resistant. There was no difference in cell lysis with the addition of the competitive cold target, suggesting that the major effect is NK-cell mediated (Figure 3A).
To confirm NK-cell-mediated killing, CD4+,
CD8+, CD56+, or CD14+ cells were
depleted from PBMCs treated with IL-2 for 72 hours and then with IMiD1
(5 µg/mL) for 72 hours. As can be seen in Figure 3B, the depletion of
CD4+ and CD8+ cells resulted in no reduction in
MM cell lysis, whereas the depletion of CD56+ cells
resulted in a significant reduction of MM cell lysis Activation antigen profile on NK cells after treatment by Thal and IMiDs Phenotypic analysis of PBMCs treated in this way showed no change in expression or absolute numbers of CD3+, CD4+, CD8+, or CD56+ cells. Further analysis of NK cell subsets demonstrated no change in the expression of activation markers CD2, CD31, CD38, CD69, or HLA-DR between control, Thal-, and ImiD-treated samples or with increasing drug concentrations (Figure 4).
Treatment of patient PBMCs with Thal and IMiDs induces increased lysis of autologous MM cells Significantly, PBMCs from patients with MM treated with IL-2 and Thal also resulted in increased killing of autologous MM cells (patient 1: DMSO control 18.4% vs Thal 31.2%, P = .03; patient 2: DMSO control 1.8% vs Thal 5.5%, P = .005) (Figure 5). As was observed with MM cell lines, the treatment of MM patient PBMCs with IMiDs resulted in an additional increase in autologous MM cell lysis (patient 1: DMSO control 18.4% vs IMiD1 51.6%, P < .001; IMiD2 49.7%, P < .001; IMiD3 45.9%, P < .001; patient 2: DMSO control 1.8% vs IMiD1 19.5%, P < .001; IMiD2 10.3%, P < .001; IMiD3 12.9%, P < .001).
Clinical relevance of NK cells in patients treated with Thal Monthly phenotypic analysis was performed on 5 patients receiving Thal treatment according to an institutional protocol. Three patients responded to treatment with Thal 200 to 800 mg/day (2 partial responses, 1 stable disease), and 2 patients failed to respond to therapy. There was no change in absolute numbers or percentages of CD3+, CD4+, or CD8+ T-cell subsets during the treatment course. All patients receiving therapy showed an increase in the absolute numbers of CD56+ NK cells (mean fold increase, 2.6; range, 1.2-3.8). The 3 patients responding to treatment showed an increase in the percentage of CD56+ NK cells (fold increases of 5.6, 2.7, and 2.1) compared to patients who failed to respond (fold increases of 0.5 and 1.2) (Table 2). Cytokine levels were also measured in the plasma at monthly intervals from all 5 patients. At the beginning of treatment, only one patient had detectable levels of IL-2 or IFN-. As demonstrated in Figure 6,
this patient achieved a good partial response, with the levels of both
cytokines significantly rising with treatment (IL-2,
P < .001; IFN-, P < .001). IL-2 and
IFN- levels remained undetectable in the other 4 patients.
Despite the use of conventional therapy, the 5-year survival of patients with MM remains poor. The introduction of high-dose therapy has resulted in an encouraging improvement in response and survival rates; however, patients eventually have relapses with refractory disease, and few, if any, are cured. Based on the observation of increased angiogenesis in the bone marrow of patients with MM, Thal was used to treat relapsed/refractory MM, and it achieved an impressive response rate of 30%.1 However, the lack of correlation of BM angiogenesis with response to Thal suggested alternative anti-MM mechanisms of action of the drug. To define other potential mechanisms of anti-MM activity, we first demonstrated in vitro a direct effect of Thal and IMiDs against human MM cell lines and patient cells, including those resistant to conventional therapy.2 These drugs either induced growth arrest or apoptosis, associated with the activation of RAFTK, in MM cell lines and patient cells. However, the effects of Thal in vitro are noted at higher concentrations than are achievable in patient plasma, suggesting that other mechanisms of action may be important in mediating its anti-MM effect. Our previous studies have delineated mechanisms whereby MM cells home, grow, and survive in the BM microenvironment,12-14 and recent studies suggest that Thal and IMiDs may impact MM through its effects on cytokines in the BM milieu (manuscript submitted). Specifically, we have demonstrated that MM cells in the BM trigger interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion. IL-6 is the major growth and survival factor in MM. Our recent studies suggest that VEGF not only mediates angiogenesis, but also directly triggers low-level proliferation and migration of human MM cells.15 Thal and the IMiDs abrogate the up-regulation of IL-6 and VEGF secretion triggered by MM cells in the BM. The inhibition of cytokine secretion therefore has an impact not only on the microenvironment, ie, angiogenesis, but also directly inhibits MM cell growth, survival, and migration. The above demonstration that Thal acts through cytokines in the BM of
patients with MM In this study, we describe a novel immunomodulatory mechanism of action of Thal and IMiDs. These drugs induced NK-cell-mediated lysis of MM cell lines and patient cells. Cold-target inhibition assays showed that this killing is NK cell rather than LAK cell mediated. Moreover, the depletion of CD56+ cells, but not of CD4+ or CD8+ cells, blocked drug-induced MM cell lysis, confirming that NK cells are the effectors mediating this response. Thal- and IMiD-induced MM cell lysis was not altered by class I or class II blocking, further implicating NK cells. To confirm the in vivo significance of the in vitro NK cell-mediated MM
cell lysis triggered by Thal, we determined whether NK cell number and
function were similarly altered in patients treated with Thal for
relapsed MM after transplantation. We demonstrate that all patients
treated with Thal show an increase in absolute number of NK cells;
however, only those patients who responded to treatment showed an
increase in the percentage of NK cells. Measurement of cytokines in the
plasma from patients also showed that the decrease in paraprotein and
the increase in NK cells was accompanied by an increase in IL-2 and
IFN-
Submitted December 20, 2000; accepted March 2, 2001.
Supported by the British Society of Haematology Fellowship (F.E.D.), the Doris Duke Distinguished Clinical Research Scientist Award (K.C.A.), and National Institutes of Health grant PO-1 78378.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth C. Anderson, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Rm M557, Boston, MA 02115; e-mail: kenneth_anderson{at}dfci.harvard.edu.
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A. Raza, J. A. Reeves, E. J. Feldman, G. W. Dewald, J. M. Bennett, H. J. Deeg, L. Dreisbach, C. A. Schiffer, R. M. Stone, P. L. Greenberg, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q Blood, January 1, 2008; 111(1): 86 - 93. [Abstract] [Full Text] [PDF]
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A. Palumbo, P. Falco, P. Corradini, A. Falcone, F. Di Raimondo, N. Giuliani, C. Crippa, G. Ciccone, P. Omede, M. T. Ambrosini, et al. Melphalan, Prednisone, and Lenalidomide Treatment for Newly Diagnosed Myeloma: A Report From the GIMEMA Italian Multiple Myeloma Network J. Clin. Oncol., October 1, 2007; 25(28): 4459 - 4465. [Abstract] [Full Text] [PDF]
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Y. M. El-Sherbiny, J. L. Meade, T. D. Holmes, D. McGonagle, S. L. Mackie, A. W. Morgan, G. Cook, S. Feyler, S. J. Richards, F. E. Davies, et al. The Requirement for DNAM-1, NKG2D, and NKp46 in the Natural Killer Cell-Mediated Killing of Myeloma Cells Cancer Res., September 15, 2007; 67(18): 8444 - 8449. [Abstract] [Full Text] [PDF]
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 N. D. Yildirim, M. Ayer, R. D. Kucukkaya, N. Alpay, O. Mete, M. N. Yenerel, A. S. Yavuz, and M. Nalcaci Leukocytoclastic Vasculitis due to Thalidomide in Multiple Myeloma Jpn. J. Clin. Oncol., September 1, 2007; 37(9): 704 - 707. [Abstract] [Full Text] [PDF]
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 A. Pellagatti, M. Jadersten, A.-M. Forsblom, H. Cattan, B. Christensson, E. K. Emanuelsson, M. Merup, L. Nilsson, J. Samuelsson, B. Sander, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients PNAS, July 3, 2007; 104(27): 11406 - 11411. [Abstract] [Full Text] [PDF]
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P. G. Richardson, C. Mitsiades, R. Schlossman, N. Munshi, and K. Anderson New Drugs for Myeloma Oncologist, June 1, 2007; 12(6): 664 - 689. [Abstract] [Full Text] [PDF]
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 A. Thornburg, R. Abonour, P. Smith, K. Knox, and H. L. Twigg III Hypersensitivity Pneumonitis-Like Syndrome Associated With the Use of Lenalidomide Chest, May 1, 2007; 131(5): 1572 - 1574. [Abstract] [Full Text] [PDF]
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C. Carlo-Stella, A. Guidetti, M. Di Nicola, C. Lavazza, L. Cleris, D. Sia, P. Longoni, M. Milanesi, M. Magni, Z. Nagy, et al. IFN-{gamma} Enhances the Antimyeloma Activity of the Fully Human Anti-Human Leukocyte Antigen-DR Monoclonal Antibody 1D09C3 Cancer Res., April 1, 2007; 67(7): 3269 - 3275. [Abstract] [Full Text] [PDF]
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D. Verhelle, L. G. Corral, K. Wong, J. H. Mueller, L. Moutouh-de Parseval, K. Jensen-Pergakes, P. H. Schafer, R. Chen, E. Glezer, G. D. Ferguson, et al. Lenalidomide and CC-4047 Inhibit the Proliferation of Malignant B Cells while Expanding Normal CD34+ Progenitor Cells Cancer Res., January 15, 2007; 67(2): 746 - 755. [Abstract] [Full Text] [PDF]
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A. Suvannasankha, C. Fausel, B. E. Juliar, C. T. Yiannoutsos, W. B. Fisher, R. H. Ansari, L. L. Wood, G. G. Smith, L. D. Cripe, and R. Abonour Final Report of Toxicity and Efficacy of a Phase II Study of Oral Cyclophosphamide, Thalidomide, and Prednisone for Patients with Relapsed or Refractory Multiple Myeloma: A Hoosier Oncology Group Trial, HEM01-21 Oncologist, January 1, 2007; 12(1): 99 - 106. [Abstract] [Full Text] [PDF]
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P. G. Richardson, E. Blood, C. S. Mitsiades, S. Jagannath, S. R. Zeldenrust, M. Alsina, R. L. Schlossman, S. V. Rajkumar, K. R. Desikan, T. Hideshima, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma Blood, November 15, 2006; 108(10): 3458 - 3464. [Abstract] [Full Text] [PDF]
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D. H. Chang, N. Liu, V. Klimek, H. Hassoun, A. Mazumder, S. D. Nimer, S. Jagannath, and M. V. Dhodapkar Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications Blood, July 15, 2006; 108(2): 618 - 621. [Abstract] [Full Text] [PDF]
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E. P. von Strandmann, H. P. Hansen, K. S. Reiners, R. Schnell, P. Borchmann, S. Merkert, V. R. Simhadri, A. Draube, M. Reiser, I. Purr, et al. A novel bispecific protein (ULBP2-BB4) targeting the NKG2D receptor on natural killer (NK) cells and CD138 activates NK cells and has potent antitumor activity against human multiple myeloma in vitro and in vivo Blood, March 1, 2006; 107(5): 1955 - 1962. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Thalidomide and Dexamethasone: A New Standard of Care for Initial Therapy in Multiple Myeloma J. Clin. Oncol., January 20, 2006; 24(3): 334 - 336. [Full Text] [PDF]
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Y.-T. Tai, X.-F. Li, L. Catley, R. Coffey, I. Breitkreutz, J. Bae, W. Song, K. Podar, T. Hideshima, D. Chauhan, et al. Immunomodulatory Drug Lenalidomide (CC-5013, IMiD3) Augments Anti-CD40 SGN-40-Induced Cytotoxicity in Human Multiple Myeloma: Clinical Implications Cancer Res., December 15, 2005; 65(24): 11712 - 11720. [Abstract] [Full Text] [PDF]
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T. Hideshima, J. E. Bradner, D. Chauhan, and K. C. Anderson Intracellular Protein Degradation and Its Therapeutic Implications Clin. Cancer Res., December 15, 2005; 11(24): 8530 - 8533. [Full Text] [PDF]
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A. Chanan-Khan, K. C. Miller, K. Takeshita, A. Koryzna, K. Donohue, Z. P. Bernstein, A. Mohr, D. Klippenstein, P. Wallace, J. B. Zeldis, et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL) Blood, November 15, 2005; 106(10): 3348 - 3352. [Abstract] [Full Text] [PDF]
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T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma J. Clin. Oncol., September 10, 2005; 23(26): 6345 - 6350. [Abstract] [Full Text] [PDF]
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M. Altun, P. J. Galardy, R. Shringarpure, T. Hideshima, R. LeBlanc, K. C. Anderson, H. L. Ploegh, and B. M. Kessler Effects of PS-341 on the Activity and Composition of Proteasomes in Multiple Myeloma Cells Cancer Res., September 1, 2005; 65(17): 7896 - 7901. [Abstract] [Full Text] [PDF]
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F. J. Hernandez-Ilizaliturri, N. Reddy, B. Holkova, E. Ottman, and M. S. Czuczman Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model Clin. Cancer Res., August 15, 2005; 11(16): 5984 - 5992. [Abstract] [Full Text] [PDF]
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A. Vacca, C. Scavelli, V. Montefusco, G. Di Pietro, A. Neri, M. Mattioli, S. Bicciato, B. Nico, D. Ribatti, F. Dammacco, et al. Thalidomide Downregulates Angiogenic Genes in Bone Marrow Endothelial Cells of Patients With Active Multiple Myeloma J. Clin. Oncol., August 10, 2005; 23(23): 5334 - 5346. [Abstract] [Full Text] [PDF]
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H. Zhang, V. Vakil, M. Braunstein, E. L. P. Smith, J. Maroney, L. Chen, K. Dai, J. R. Berenson, M. M. Hussain, U. Klueppelberg, et al. Circulating endothelial progenitor cells in multiple myeloma: implications and significance Blood, April 15, 2005; 105(8): 3286 - 3294. [Abstract] [Full Text] [PDF]
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K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
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 A. List, S. Kurtin, D. J. Roe, A. Buresh, D. Mahadevan, D. Fuchs, L. Rimsza, R. Heaton, R. Knight, and J. B. Zeldis Efficacy of Lenalidomide in Myelodysplastic Syndromes N. Engl. J. Med., February 10, 2005; 352(6): 549 - 557. [Abstract] [Full Text] [PDF]
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B. I. Rini and E. J. Small Biology and Clinical Development of Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma J. Clin. Oncol., February 10, 2005; 23(5): 1028 - 1043. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, P. G. Richardson, T. Hideshima, and K. C. Anderson Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer J. Clin. Oncol., January 20, 2005; 23(3): 630 - 639. [Abstract] [Full Text] [PDF]
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E. Carbone, P. Neri, M. Mesuraca, M. T. Fulciniti, T. Otsuki, D. Pende, V. Groh, T. Spies, G. Pollio, D. Cosman, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells Blood, January 1, 2005; 105(1): 251 - 258. [Abstract] [Full Text] [PDF]
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H. Kaufmann, M. Raderer, S. Wohrer, A. Puspok, A. Bankier, C. Zielinski, A. Chott, and J. Drach Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma Blood, October 15, 2004; 104(8): 2269 - 2271. [Abstract] [Full Text] [PDF]
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 S. K. Teo, K. H. Denny, D. I. Stirling, S. D. Thomas, S. Morseth, and A. M. Hoberman Effects of Thalidomide on Developmental, Peri- and Postnatal Function in Female New Zealand White Rabbits and Offspring Toxicol. Sci., October 1, 2004; 81(2): 379 - 389. [Abstract] [Full Text] [PDF]
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P. Richardson and K. Anderson Immunomodulatory Analogs of Thalidomide: An Emerging New Therapy in Myeloma J. Clin. Oncol., August 15, 2004; 22(16): 3212 - 3214. [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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 P. Richardson, R. Schlossman, S. Jagannath, M. Alsina, R. Desikan, E. Blood, E. Weller, C. Mitsiades, T. Hideshima, F. Davies, et al. Thalidomide for Patients With Relapsed Multiple Myeloma After High-Dose Chemotherapy and Stem Cell Transplantation: Results of an Open-Label Multicenter Phase 2 Study of Efficacy, Toxicity, and Biological Activity Mayo Clin. Proc., July 1, 2004; 79(7): 875 - 882. [Abstract] [PDF]
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S. V. Rajkumar Thalidomide: Tragic Past and Promising Future Mayo Clin. Proc., July 1, 2004; 79(7): 899 - 903. [PDF]
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S. Kumar, T. E. Witzig, and S. V. Rajkumar Thalidomide: Current Role in the Treatment of Non-Plasma Cell Malignancies J. Clin. Oncol., June 15, 2004; 22(12): 2477 - 2488. [Abstract] [Full Text] [PDF]
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R. LeBlanc, T. Hideshima, L. P. Catley, R. Shringarpure, R. Burger, N. Mitsiades, C. Mitsiades, P. Cheema, D. Chauhan, P. G. Richardson, et al. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway Blood, March 1, 2004; 103(5): 1787 - 1790. [Abstract] [Full Text] [PDF]
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 J.-L. Harousseau, J. Shaughnessy Jr., and P. Richardson Multiple Myeloma Hematology, January 1, 2004; 2004(1): 237 - 256. [Abstract] [Full Text] [PDF]
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A. F. List, J. Vardiman, J.-P. J. Issa, and T. M. DeWitte Myelodysplastic Syndromes Hematology, January 1, 2004; 2004(1): 297 - 317. [Abstract] [Full Text] [PDF]
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M. S. Gee, S. Makonnen, K. al-Kofahi, B. Roysam, F. Payvandi, H.-W. Man, G. W. Muller, and W. M. F. Lee Selective Cytokine Inhibitory Drugs with Enhanced Antiangiogenic Activity Control Tumor Growth through Vascular Inhibition Cancer Res., December 1, 2003; 63(23): 8073 - 8078. [Abstract] [Full Text] [PDF]
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M. A. Dimopoulos, A. Anagnostopoulos, and D. Weber Treatment of Plasma Cell Dyscrasias With Thalidomide and Its Derivatives J. Clin. Oncol., December 1, 2003; 21(23): 4444 - 4454. [Abstract] [Full Text] [PDF]
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T. Hayashi, T. Hideshima, M. Akiyama, N. Raje, P. Richardson, D. Chauhan, and K. C. Anderson Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes Blood, August 15, 2003; 102(4): 1435 - 1442. [Abstract] [Full Text] [PDF]
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 P. H. Schafer, A. K. Gandhi, M. A. Loveland, R. S. Chen, H.-W. Man, P. P. M. Schnetkamp, G. Wolbring, S. Govinda, L. G. Corral, F. Payvandi, et al. Enhancement of Cytokine Production and AP-1 Transcriptional Activity in T Cells by Thalidomide-Related Immunomodulatory Drugs J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1222 - 1232. [Abstract] [Full Text] [PDF]
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G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF]
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S. Kumar, M. A. Gertz, A. Dispenzieri, M. Q. Lacy, S. M. Geyer, N. L. Iturria, R. Fonseca, S. R. Hayman, J. A. Lust, R. A. Kyle, et al. Response Rate, Durability of Response, and Survival After Thalidomide Therapy for Relapsed Multiple Myeloma Mayo Clin. Proc., January 1, 2003; 78(1): 34 - 39. [Abstract] [PDF]
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S. Yaccoby, C. L. Johnson, S. C. Mahaffey, M. J. Wezeman, B. Barlogie, and J. Epstein Antimyeloma efficacy of thalidomide in the SCID-hu model Blood, December 1, 2002; 100(12): 4162 - 4168. [Abstract] [Full Text] [PDF]
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 M. Mohty, A.-M. Stoppa, D. Blaise, D. Isnardon, J.-A. Gastaut, D. Olive, and B. Gaugler Differential regulation of dendritic cell function by the immunomodulatory drug thalidomide J. Leukoc. Biol., November 1, 2002; 72(5): 939 - 945. [Abstract] [Full Text] [PDF]
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K. Neben, T. Moehler, A. Benner, A. Kraemer, G. Egerer, A. D. Ho, and H. Goldschmidt Dose-dependent Effect of Thalidomide on Overall Survival in Relapsed Multiple Myeloma Clin. Cancer Res., November 1, 2002; 8(11): 3377 - 3382. [Abstract] [Full Text] [PDF]
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P. G. Richardson, R. L. Schlossman, E. Weller, T. Hideshima, C. Mitsiades, F. Davies, R. LeBlanc, L. P. Catley, D. Doss, K. Kelly, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma Blood, October 16, 2002; 100(9): 3063 - 3067. [Abstract] [Full Text] [PDF]
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Y. Miura, C. J. Thoburn, E. C. Bright, W. Chen, S. Nakao, and A. D. Hess Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD Blood, September 18, 2002; 100(7): 2650 - 2658. [Abstract] [Full Text] [PDF]
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 T. Hayashi, T. Hideshima, M. Akiyama, P. Richardson, R. L. Schlossman, D. Chauhan, N. C. Munshi, S. Waxman, and K. C. Anderson Arsenic Trioxide Inhibits Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment Mol. Cancer Ther., August 1, 2002; 1(10): 851 - 860. [Abstract] [Full Text] [PDF]
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S. V. Rajkumar, R. A. Mesa, R. Fonseca, G. Schroeder, M. F. Plevak, A. Dispenzieri, M. Q. Lacy, J. A. Lust, T. E. Witzig, M. A. Gertz, et al. Bone Marrow Angiogenesis in 400 Patients with Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Primary Amyloidosis Clin. Cancer Res., July 1, 2002; 8(7): 2210 - 2216. [Abstract] [Full Text] [PDF]
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 L. Tsenova, B. Mangaliso, G. Muller, Y. Chen, V. H. Freedman, D. Stirling, and G. Kaplan Use of IMiD3, a Thalidomide Analog, as an Adjunct to Therapy for Experimental Tuberculous Meningitis Antimicrob. Agents Chemother., June 1, 2002; 46(6): 1887 - 1895. [Abstract] [Full Text] [PDF]
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N. Mitsiades, C. S. Mitsiades, V. Poulaki, D. Chauhan, P. G. Richardson, T. Hideshima, N. C. Munshi, S. P. Treon, and K. C. Anderson Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications Blood, May 29, 2002; 99(12): 4525 - 4530. [Abstract] [Full Text] [PDF]
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K. Dredge, J. B. Marriott, S. M. Todryk, G. W. Muller, R. Chen, D. I. Stirling, and A. G. Dalgleish Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity J. Immunol., May 15, 2002; 168(10): 4914 - 4919. [Abstract] [Full Text] [PDF]
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 T. Hideshima, D. Chauhan, P. Richardson, C. Mitsiades, N. Mitsiades, T. Hayashi, N. Munshi, L. Dang, A. Castro, V. Palombella, et al. NF-kappa B as a Therapeutic Target in Multiple Myeloma J. Biol. Chem., May 3, 2002; 277(19): 16639 - 16647. [Abstract] [Full Text] [PDF]
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S. Lentzsch, M. S. Rogers, R. LeBlanc, A. E. Birsner, J. H. Shah, A. M. Treston, K. C. Anderson, and R. J. D'Amato S-3-Amino-phthalimido-glutarimide Inhibits Angiogenesis and Growth of B-Cell Neoplasias in Mice Cancer Res., April 1, 2002; 62(8): 2300 - 2305. [Abstract] [Full Text] [PDF]
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M. A. Hussein Nontraditional Cytotoxic Therapies for Relapsed/Refractory Multiple Myeloma Oncologist, April 1, 2002; 7(90001): 20 - 29. [Abstract] [Full Text] [PDF]
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A. F. List New Approaches to the Treatment of Myelodysplasia Oncologist, April 1, 2002; 7(90001): 39 - 49. [Abstract] [Full Text] [PDF]
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S. Majumdar, B. Lamothe, and B. B. Aggarwal Thalidomide Suppresses NF-{kappa}B Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester J. Immunol., March 15, 2002; 168(6): 2644 - 2651. [Abstract] [Full Text] [PDF]
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K. C. Anderson, J. D. Shaughnessy Jr., B. Barlogie, J.-L. Harousseau, and G. D. Roodman Multiple Myeloma Hematology, January 1, 2002; 2002(1): 214 - 240. [Abstract] [Full Text]
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H. G. Drexler, R. A. F. MacLeod, and W. G. Dirks Cross-contamination: HS-Sultan is not a myeloma but a Burkitt lymphoma cell line Blood, December 1, 2001; 98(12): 3495 - 3496. [Full Text] [PDF]
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W. S. Dalton, P. L. Bergsagel, W. M. Kuehl, K. C. Anderson, and J. L. Harousseau Multiple Myeloma Hematology, January 1, 2001; 2001(1): 157 - 177. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
CD56+
cells in patients responding to therapy. Thus in vitro and in vivo data
support the hypothesis that Thal may mediate its anti-MM effect, at
least in part, by modulating NK cell number and function.
(Blood. 2001;98:210-216)
(TNF-
and IL-6 secretion from PBMCs; hence, these drugs have been
named IMiDs.
),
CD4+ (
), and CD8+ (
) cells were selected
using immunomagnetic beads. Cells were stimulated with anti-CD3 and
treated with Thal (left panel) and IMiD2 (right panel) daily for 5 days. Proliferation was assayed as described above in the presence of
Thal/IMiD2 (0.1, 1, and 5 µg/mL).
decreases from
62.4% to 6.8% for HS Sultan cells and from 30.3% to 8.8% for MM1.S
cells (P < .001). Lack of involvement of cytotoxic T cells was further suggested because there was no decrease in MM cell
lysis in the presence of class I and II blocking antibodies (Figure
T cells
mediating specific lysis against MM cell lines in vitro and in
pamidronate-treated BM cultures compared to untreated control cultures.
That report, coupled with the present study, highlights the importance
of assessing the action of potential new drugs in MM not only for their
direct effect on tumor cells but also for their impact on the BM
microenvironment and host immune response. These new insights not only
lead to a better understanding of MM pathogenesis, they may also help to define at what stage of disease a therapy should be most
effective. Specifically, our results suggest that Thal and new
analogues may not only be useful in the treatment of
refractory/relapsed disease, but also be effective in the maintenance
of minimal residual disease after transplantation by enhancing
NK-cell-mediated anti-MM cell immunity.