Combination therapy for adult T-cell leukemia–xenografted mice: flavopiridol and anti-CD25 monoclonal antibody

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1231-1236 ◽  
Author(s):  
Meili Zhang ◽  
Zhuo Zhang ◽  
Carolyn K. Goldman ◽  
John Janik ◽  
Thomas A. Waldmann
Keyword(s):  
T Cell ◽  
Therapeutic Efficacy ◽  
Leukemic Cells ◽  
Control Group ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractAdult T-cell leukemia (ATL) develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1. The leukemia consists of an overabundance of activated T cells, which express CD25 on their cell surfaces. Presently, there is no accepted curative therapy for ATL. Flavopiridol, an inhibitor of cyclin-dependent kinases, has potent antiproliferative effects and antitumor activity. We investigated the therapeutic efficacy of flavopiridol alone and in combination with humanized anti-Tac antibody (HAT), which recognizes CD25, in a murine model of human ATL. The ATL model was established by intraperitoneal injection of MET-1 leukemic cells into nonobese diabetic/severe combined immunodeficient mice. Either flavopiridol, given 2.5 mg/kg body weight daily for 5 days, or HAT, given 100 μg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human β-2-microglobulin (β2μ; P < .01), and prolonged survival of the leukemia-bearing mice (P < .05) as compared with the control group. Combination of the 2 agents dramatically enhanced the antitumor effect, as shown by both β2μ levels and survival of the mice, when compared with those in the flavopiridol or HAT alone group (P < .01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.

scholarly journals Effective treatment of a murine model of adult T-cell leukemia using depsipeptide and its combination with unmodified daclizumab directed toward CD25

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1287-1293 ◽  
Author(s):  
Jing Chen ◽  
Meili Zhang ◽  
Wei Ju ◽  
Thomas A. Waldmann
Keyword(s):  
T Cell ◽  
Murine Model ◽  
Therapeutic Efficacy ◽  
Severe Combined Immunodeficiency ◽  
Control Group ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Antitumor Effects ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract Adult T-cell leukemia (ATL) is caused by human T-cell lymphotropic virus I (HTLV-1) and is an aggressive malignancy of CD4, CD25-expressing leukemia, and lymphoma cells. There is no accepted curative therapy for ATL. Depsipeptide, a histone deacetylase inhibitor, has demonstrated major antitumor effects in leukemias and lymphomas. In this study, we investigated the therapeutic efficacy of depsipeptide alone and in combination with daclizumab (humanized anti-Tac) in a murine model of human ATL. The Met-1 ATL model was established by intraperitoneal injection of ex vivo leukemic cells into nonobese diabetic/severe combined immunodeficiency mice. Either depsipeptide, given at 0.5 mg/kg every other day for 2 weeks, or daclizumab, given at 100 μg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of soluble IL-2R-α (sIL-2R-α) and soluble β2-microglobulin (β2μ) (P < .001), and prolonged survival of the leukemia-bearing mice (P < .001) compared with the control group. Combination of depsipeptide with daclizumab enhanced the antitumor effect, as shown by both sIL-2R-α and β2μ levels and survival of the leukemia-bearing mice, compared with those in the depsipeptide or daclizumab alone groups (P < .001). The significantly improved therapeutic efficacy by combining depsipeptide with daclizumab supports a clinical trial of this combination in the treatment of ATL.

scholarly journals A model of in vivo cell proliferation of adult T-cell leukemia

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2501-2509 ◽  
Author(s):  
A Kondo ◽  
K Imada ◽  
T Hattori ◽  
H Yamabe ◽  
T Tanaka ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Scid Mice ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Beta Chain ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract We have made a model of in vivo cell proliferation of leukemic cells from adult T-cell leukemia (ATL) patients using severe combined immunodeficiency (SCID) mice. Peripheral blood mononuclear cells (PBMC) or lymph node cells (LNC) depleted of B cells and monocytes were intraperitoneally injected into SCID mice treated with antimurine interleukin-2 receptor (IL-2+) beta chain monoclonal antibody (MoAb)(TM- beta 1), followed by daily injection of human recombinant IL-2 until 60 days after cell injection. SCID mice injected with ATL cells from 6 of 8 ATL patients were found to have the tumor or leukemia 5 to 7 weeks after the inoculation of cells. Serum levels of soluble form of human IL-2R alpha chain (Tac) were markedly elevated in such mice. The cells recovered from the mice injected with leukemic cells from four different ATL patients had the same cell surface phenotype as that of original leukemic cells which were CD4+Tac+. Furthermore, we detected the same integration site of human T-cell leukemia virus type I (HTLV- I) provirus and the same rearrangement pattern of human T-cell receptor (TCR) beta chain gene as those of ATL cells by Southern blot hybridization, indicating that the cells proliferating in SCID mice were derived from the original ATL cell clone. Histologic examination showed that the pattern of the infiltration of ATL cells into various organs in SCID mice was similar to that of an ATL patient. Such a model of in vivo cell proliferation of ATL cells will be useful for the study of the mechanism of neoplastic cell proliferation and for the development of a new and effective treatment of ATL.

How I treat adult T-cell leukemia/lymphoma

Blood ◽  
2011 ◽  
Vol 118 (7) ◽  
pp. 1736-1745 ◽  
Author(s):  
Ali Bazarbachi ◽  
Felipe Suarez ◽  
Paul Fields ◽  
Olivier Hermine
Keyword(s):  
T Cell ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Activated T Cells ◽  
Term Survival ◽  
Long Term Survival ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractAdult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T cells caused by human T-cell lymphotropic virus type I. ATL carries a bad prognosis because of intrinsic chemoresistance and severe immunosuppression. In acute ATL, Japanese trials demonstrated that although combinations of chemotherapy improved response rate, they failed to achieve a significant impact on survival. Patients with chronic and smoldering ATL have a better prognosis, but long-term survival is poor when these patients are managed with a watchful-waiting policy or with chemotherapy. Recently, a worldwide meta-analysis revealed that the combination of zidovudine and IFN-α is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. ATL lymphoma patients still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine/IFN. To prevent relapse, clinical trials assessing consolidative targeted therapies such as arsenic/IFN combination or novel monoclonal antibodies are needed. Finally, allogeneic BM transplantation should be considered in suitable patients.

scholarly journals Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1007-1012 ◽  
Author(s):  
Zhuo Zhang ◽  
Meili Zhang ◽  
Kayhan Garmestani ◽  
Vladimir S. Talanov ◽  
Paul S. Plascjak ◽  
...  
Keyword(s):  
T Cell ◽  
Therapeutic Efficacy ◽  
Severe Combined Immunodeficiency ◽  
Treated Group ◽  
Survival Duration ◽  
Combination Group ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractAdult T-cell leukemia (ATL) consists of an overabundance of T cells, which express CD25. Therapeutic efficacy of astatine-211 (211At)–labeled murine monoclonal antibody 7G7/B6 alone and in combination with daclizumab was evaluated in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice given injections of MET-1 human T-cell leukemia cells. Daclizumab and 7G7/B6 are directed toward different epitopes of CD25. Either a single dose of 12 μCi (0.444 MBq) 211At-7G7/B6 per mouse given intravenously or receptor-saturating doses of daclizumab given at 100 μg weekly for 4 weeks intravenously inhibited tumor growth as monitored by serum levels of human β-2 microglobulin (β2μ) and by prolonged survival of leukemia-bearing mice compared with the control groups (P < .001). The combination of 2 agents enhanced the antitumor effect when compared with groups treated with 12 μCi (0.444 MBq) of 211At-7G7/B6 (P < .05) or daclizumab alone (P < .05). The median survival duration of the PBS group was 62.6 days and 61.5 days in the radiolabeled nonspecific antibody 211At-11F11–treated group. In contrast, 91% of mice in the combination group survived through day 94. These results that demonstrate a significantly improved therapeutic efficacy by combining 211At-7G7/B6 with daclizumab support a clinical trial of this regimen in patients with ATL.

Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1150-1159 ◽  
Author(s):  
Tobias Ruckes ◽  
Domenica Saul ◽  
Jacques Van Snick ◽  
Olivier Hermine ◽  
Ralph Grassmann
Keyword(s):  
T Cell ◽  
Cultured Cells ◽  
Human Lymphocytes ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
Antiapoptotic Activity

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+ T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemogenesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the expression of distinct cellular genes. Alterations in the expression levels of unknown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked to Tax transformation and ATL leukemogenesis, this study systematically compared the gene expression of cultured cells from patients with acute ATL with that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These include a dual-specific protein phosphatase (PAC1), an interferon-inducible factor (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) signaling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309–specific antiapoptotic activity and the proapoptotic effect of inhibitors of I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apoptosis in ATL cells and could substantially contribute to their growth.

Adult T-cell leukemia/lymphoma comprising non-floral leukemic cells in Taiwan, a country non-endemic for human T-cell leukemia virus type I

2009 ◽  
Vol 50 (9) ◽  
pp. 1540-1542 ◽  
Author(s):  
Yen-Chuan Hsieh ◽  
Sheng-Tsung Chang ◽  
Wen-Tsung Huang ◽  
Ryo Ichinohasama ◽  
Shih-Sung Chuang
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Leukemic Cells ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

scholarly journals Constitutive overexpression of the L-selectin gene in fresh leukemic cells of adult T-cell leukemia that can be transactivated by human T- cell lymphotropic virus type 1 Tax

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 3109-3117 ◽  
Author(s):  
M Tatewaki ◽  
K Yamaguchi ◽  
M Matsuoka ◽  
T Ishii ◽  
M Miyasaka ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Vascular Endothelium ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

L-selectin is an adhesion molecule of the selectin family that mediates the initial step of leukocyte adhesion to vascular endothelium. Upon cellular activation, expression of the L-selectin gene is downregulated at both the protein and mRNA levels. To understand the mechanism of leukemic cell infiltration into organs, we studied the expression and regulation of L-selectin mRNA in fresh leukemic cells of adult T-cell leukemia (ATL) patients and investigated the response of the L-selectin promoter to human T-cell lymphotropic virus type 1 (HTLV-1) Tax, which is a viral transcriptional transactivator. Flow cytometry showed that L-selectin was expressed on fresh ATL cells along with other activation antigens. Northern blot analysis showed that ATL cells overexpressed that L-selectin mRNA and that the level was aberrantly upregulated after PMA stimulation. Studies using in situ hybridization showed expression of the L-selectin mRNA in the infiltrating leukemic cells in the liver of two ATL patients. Intravenous injection of a rat T-cell line that overexpresses L-selectin showed increased organ infiltration. The induction of Tax expression in JPX9 cells resulted in about a twofold increase in the mRNA expression levels compared with the basal level. Chloramphenicol acetyltransferase (CAT) assay after transient cotransfection showed about a fivefold transactivation of the L-selectin promoter by Tax. The serum level of the shed form of L-selectin was significantly increased in ATL patients (mean +/- SD, 4,215.4 +/- 4,111 ng/mL) compared with those of asymptomatic carriers and healthy blood donors (mean +/- SD, 1,148.0 +/- 269.0 ng/mL and 991.9 +/- 224 ng/mL, respectively). These results indicated that ATL cells constitutively overexpress the L-selectin gene that can be transactivated by HTLV-1 Tax. The overexpression of L-selectin, as well as of inflammatory cytokines, by ATL cells may provide a basis for ATL cells to attach the vascular endothelium, leading to transmigration and organ infitration.

scholarly journals A model of in vivo cell proliferation of adult T-cell leukemia

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2501-2509 ◽  
Author(s):  
A Kondo ◽  
K Imada ◽  
T Hattori ◽  
H Yamabe ◽  
T Tanaka ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Scid Mice ◽  
Leukemic Cells ◽  
T Cell Leukemia ◽  
Beta Chain ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Human T Cell

We have made a model of in vivo cell proliferation of leukemic cells from adult T-cell leukemia (ATL) patients using severe combined immunodeficiency (SCID) mice. Peripheral blood mononuclear cells (PBMC) or lymph node cells (LNC) depleted of B cells and monocytes were intraperitoneally injected into SCID mice treated with antimurine interleukin-2 receptor (IL-2+) beta chain monoclonal antibody (MoAb)(TM- beta 1), followed by daily injection of human recombinant IL-2 until 60 days after cell injection. SCID mice injected with ATL cells from 6 of 8 ATL patients were found to have the tumor or leukemia 5 to 7 weeks after the inoculation of cells. Serum levels of soluble form of human IL-2R alpha chain (Tac) were markedly elevated in such mice. The cells recovered from the mice injected with leukemic cells from four different ATL patients had the same cell surface phenotype as that of original leukemic cells which were CD4+Tac+. Furthermore, we detected the same integration site of human T-cell leukemia virus type I (HTLV- I) provirus and the same rearrangement pattern of human T-cell receptor (TCR) beta chain gene as those of ATL cells by Southern blot hybridization, indicating that the cells proliferating in SCID mice were derived from the original ATL cell clone. Histologic examination showed that the pattern of the infiltration of ATL cells into various organs in SCID mice was similar to that of an ATL patient. Such a model of in vivo cell proliferation of ATL cells will be useful for the study of the mechanism of neoplastic cell proliferation and for the development of a new and effective treatment of ATL.

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