Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD2 monoclonal antibody, MEDI-507

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 284-288 ◽  
Author(s):  
Zhuo Zhang ◽  
Meili Zhang ◽  
Jeffrey V. Ravetch ◽  
Carolyn Goldman ◽  
Thomas A. Waldmann
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Polymorphonuclear Leukocytes ◽  
Prolonged Treatment ◽  
Control Group ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Tumor Killing

Abstract Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with the retrovirus human T-cell leukemia virus (HTLV-1). We evaluated the efficacy of MEDI-507 (a humanized monoclonal antibody directed against CD2) alone and in combination with humanized anti-Tac (HAT) directed toward CD25, the interleukin-2 receptor α (IL-2Rα) using a human adult T-cell leukemia xenograft model. Weekly treatments (4) with HAT significantly prolonged the survival of the ATL-bearing mice when compared with phosphate-buffered saline (PBS)–treated controls (P < .0001). Mice treated with MEDI-507 (100 μg/wk for 4 weeks) survived longer than those treated with HAT (P < .0025). Furthermore, prolonged treatment (6 months) of ATL with MEDI-507 significantly improved the outcome when compared with a short course (4 weeks) of therapy (P < .0036). Such treatment with weekly MEDI-507 for 6 months led to a prolonged survival of the ATL-bearing mice that was comparable with the survival observed in the control group of mice that did not receive a tumor or therapeutic agent. We also found that the expression of Fcγ receptors (FcRγ) on polymorphonuclear leukocytes and monocytes was required for MEDI-507–mediated tumor killing in vivo. Thus, the tumor-killing mechanism with MEDI-507 in vivo required the expression of the receptor FcRγIII on polymorphonuclear leukocytes and monocytes, suggesting that it is mediated by a form of antibody-dependent cellular cytotoxicity. These results demonstrate that MEDI-507 has therapeutic efficacy on ATL in vivo and provides support for a clinical trial involving this monoclonal antibody in the treatment of patients with CD2-expressing leukemias and lymphomas. (Blood. 2003; 102:284-288)

scholarly journals In vivo effects of murine hybridoma monoclonal antibody in a patient with T-cell leukemia

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 78-86 ◽  
Author(s):  
RA Miller ◽  
DG Maloney ◽  
J McKillop ◽  
R Levy
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Antibody Therapy ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Antigenic Modulation ◽  
Adult T Cell Leukemia ◽  
Free Antigen

Abstract A murine monoclonal antibody directed against a normal T-cell differentiation antigen was given to a patient with adult T-cell leukemia. Immunofluorescence staining showed increased amounts of this antigen on the patient's leukemia cells. Using a competition radioimmunoassay, free antigen was not detectable in the serum prior to therapy. Two courses of in vivo therapy were given using a 1-mg dose. Each produced a prompt and dramatic fall in WBC with return to pretreatment levels over the ensuing 24 hr, a pattern similar to that seen with leukopheresis. After the first dose of antibody, circulating free antigen became detectable in the serum and a transient decline in creatinine clearance was noted. A 5-mg dose of antibody given at that time was ineffective, presumably because it was blocked by free antigen. Antigenic modulation by leukemia cells was found transiently following each course of antibody. A weak and clinically insignificant host antimouse antibody response was found 5 days after the first treatment. The patient tolerated antibody therapy without difficulty. Monoclonal antibodies offer promise as an immunotherapeutic approach to cancer but problems encountered here must be addressed.

scholarly journals In vivo effects of murine hybridoma monoclonal antibody in a patient with T-cell leukemia

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 78-86
Author(s):  
RA Miller ◽  
DG Maloney ◽  
J McKillop ◽  
R Levy
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Antibody Therapy ◽  
Leukemia Cells ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Antigenic Modulation ◽  
Adult T Cell Leukemia ◽  
Free Antigen

A murine monoclonal antibody directed against a normal T-cell differentiation antigen was given to a patient with adult T-cell leukemia. Immunofluorescence staining showed increased amounts of this antigen on the patient's leukemia cells. Using a competition radioimmunoassay, free antigen was not detectable in the serum prior to therapy. Two courses of in vivo therapy were given using a 1-mg dose. Each produced a prompt and dramatic fall in WBC with return to pretreatment levels over the ensuing 24 hr, a pattern similar to that seen with leukopheresis. After the first dose of antibody, circulating free antigen became detectable in the serum and a transient decline in creatinine clearance was noted. A 5-mg dose of antibody given at that time was ineffective, presumably because it was blocked by free antigen. Antigenic modulation by leukemia cells was found transiently following each course of antibody. A weak and clinically insignificant host antimouse antibody response was found 5 days after the first treatment. The patient tolerated antibody therapy without difficulty. Monoclonal antibodies offer promise as an immunotherapeutic approach to cancer but problems encountered here must be addressed.

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.

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 Effect of a novel anti-CCR4 monoclonal antibody (Mogamulizmab) on skin lesions of adult T-cell leukemia-lymphoma (ATL) and its adverse skin reactions (ASR)

Retrovirology ◽  
2014 ◽  
Vol 11 (S1) ◽  
Author(s):  
Kentaro Yonekura ◽  
Tamotsu Kanzaki ◽  
Nobuaki Nakano ◽  
Masahito Tokunaga ◽  
Ayumu Kubota ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Skin Lesions ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Skin Reactions ◽  
Adult T Cell Leukemia

Zidovudine Blocks NF-κB activity in Vivo in Adult T-Cell Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2524-2524 ◽  
Author(s):  
Juan Carlos Ramos ◽  
Luis M. Diaz ◽  
Michele Manrique ◽  
Rosangela Lima ◽  
Ngoc L Toomey ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Alpha ◽  
Phase Ii ◽  
Target Genes ◽  
Recent Analysis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Resistant Disease

Abstract Adult T-cell leukemia (ATL) is a lymphoid malignancy caused by the human T-cell leukemia virus type I (HTLV-I), which carries a poor prognosis. A hallmark of ATL is the high constitutive expression of NF-κB, which predominantly exerts an anti-apoptotic effect contributing to chemotherapy resistance. Many of the elegant studies about the pathogenesis of ATL have focused on Tax, a viral transactivator of NF-κB, using HTLV-I expressing cell lines and mouse models, however in primary tumors the virus remains latent and Tax is not detected. We and other investigators have demonstrated the clinical efficacy of Zidovudine (AZT) and interferon-alpha (IFNα) combination therapy in both chronic and acute ATL subtypes with some patients achieving clinical remission or stable disease for many years while on maintenance therapy. The exact mechanisms of these antiviral drugs in ATL remain unclear. In a recent analysis of primary ATL tumors, we implicated the expression of both c-Rel and the NF-κB target gene product IRF-4/MUM-1 in AZT/IFN resistant disease. We have recently opened to accrual a Phase II clinical trial titled Prospective Study of the Molecular Characteristics of Sensitive and Resistant Disease in Patients with HTLV-I Associated Adult T Cell Leukemia Treated with Zidovudine Plus Interferon alpha-2b, which includes the novel use of pegylated interferon-alpha and valproic acid (as HDAC inhibitor) in the maintenance phase as an attempt to eradicate residual ATL clones, which usually occurs after AZT and IFNα therapy even after longterm remission. Our goals are also to study the anti-tumor mechanisms of these drugs in ATL, and define molecular criteria for response. As part of the correlative studies in our Phase II trial, we have analyzed leukemic ATL cells collected from patients during the first 48 hours of treatment (AZT given alone prior to IFN) and found in vivo stabilization of IκB (the repressor protein of NF-κB) by Western Blot in patients responding to the treatment, suggesting a role for this antiviral drug in blocking NF-κB activity as previously hypothesized in our laboratory. We also examined the expression of NF-κB related genes using a custom designed gene expression array by a novel technology (NanoString Inc.) of selected NF-κB target genes and found downregulation of most these genes in vivo by AZT alone. So far, all ATL tumors analyzed exhibited high expression of many NF-κB target genes, and over forty of these are differentially overexpressed in ATL specimens as compared to normal CD4+ T-cells. Some the differentially expressed genes include those encoding NF-κB/Rel, interferon regulatory factor (IRF), and bcl-2 related proteins. A comprehensive analysis of over forty ATL tumors, including specimens collected in both Miami and Brazil, is ongoing and expected to be completed soon. Baseline tumor characteristics and prognostic variables of previously collected tumors, as well interim results of our clinical and molecular studies will be reported.

scholarly journals Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

Blood ◽  
2017 ◽  
Vol 129 (9) ◽  
pp. 1071-1081 ◽  
Author(s):  
Toshiki Watanabe
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
New Findings

Abstract Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) that develops through a multistep carcinogenesis process involving 5 or more genetic events. We provide a comprehensive overview of recently uncovered information on the molecular basis of leukemogenesis in ATL. Broadly, the landscape of genetic abnormalities in ATL that include alterations highly enriched in genes for T-cell receptor–NF-κB signaling such as PLCG1, PRKCB, and CARD11 and gain-of function mutations in CCR4 and CCR7. Conversely, the epigenetic landscape of ATL can be summarized as polycomb repressive complex 2 hyperactivation with genome-wide H3K27 me3 accumulation as the basis of the unique transcriptome of ATL cells. Expression of H3K27 methyltransferase enhancer of zeste 2 was shown to be induced by HTLV-1 Tax and NF-κB. Furthermore, provirus integration site analysis with high-throughput sequencing enabled the analysis of clonal composition and cell number of each clone in vivo, whereas multicolor flow cytometric analysis with CD7 and cell adhesion molecule 1 enabled the identification of HTLV-1–infected CD4+ T cells in vivo. Sorted immortalized but untransformed cells displayed epigenetic changes closely overlapping those observed in terminally transformed ATL cells, suggesting that epigenetic abnormalities are likely earlier events in leukemogenesis. These new findings broaden the scope of conceptualization of the molecular mechanisms of leukemogenesis, dissecting them into immortalization and clonal progression. These recent findings also open a new direction of drug development for ATL prevention and treatment because epigenetic marks can be reprogrammed. Mechanisms underlying initial immortalization and progressive accumulation of these abnormalities remain to be elucidated.

scholarly journals Prevention of Adult T-Cell Leukemia-Like Lymphoproliferative Disease in Rats by Adoptively Transferred T Cells from a Donor Immunized with Human T-Cell Leukemia Virus Type 1 Tax-Coding DNA Vaccine

2000 ◽  
Vol 74 (20) ◽  
pp. 9610-9616 ◽  
Author(s):  
Takashi Ohashi ◽  
Shino Hanabuchi ◽  
Hirotomo Kato ◽  
Hiromi Tateno ◽  
Fumiyo Takemura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) in infected individuals after a long incubation period. To dissect the mechanisms of the development of the disease, we have previously established a rat model of ATL-like disease which allows examination of the growth and spread of HTLV-1 infected tumor cells, as well assessment of the effects of immune T cells on the development of the disease. In the present study, we induced HTLV-1 Tax-specific cytotoxic T lymphocyte (CTL) immunity by vaccination with Tax-coding DNA and examined the effects of the DNA vaccine in our rat ATL-like disease model. Our results demonstrated that DNA vaccine with Tax effectively induced Tax-specific CTL activity in F344/N Jcl-rnu/+ (nu/+) rats and that these CTLs were able to lyse HTLV-1 infected syngeneic T cells in vitro. Adoptive transfer of these immune T cells effectively inhibited the in vivo growth of HTLV-1-transformed tumor in F344/N Jcl-rnu/rnu (nu/nu) rats inoculated with a rat HTLV-1 infected T cell line. Vaccination with mutant Tax DNA lacking transforming ability also induced efficient anti-tumor immunity in this model. Our results indicated a promising effect for DNA vaccine with HTLV-1 Tax against HTLV-1 tumor development in vivo.

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