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  • 1
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    Online Resource
    Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability
    American Society of Hematology ; 2009
    In:  Blood Vol. 113, No. 17 ( 2009-04-23), p. 4016-4026
    Details
    In: Blood, American Society of Hematology, Vol. 113, No. 17 ( 2009-04-23), p. 4016-4026
    Abstract: Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-α, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to “central” genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-08-175901
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
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    Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1–Associated Adult T-cell Leukemia/lymphoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 1 ( 2017-01-01), p. 35-42
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 1 ( 2017-01-01), p. 35-42
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1022
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
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    Yttrium-90 Radiolabeled Daclizumab, An Anti-CD25 Monoclonal Antibody, Provides Effective Therapy for Refractory and Relapsed Hodgkin's Lymphoma,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3706-3706
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3706-3706
    Abstract: Abstract 3706 Despite the success of treatment of patients with refractory and relapsed Hodgkin's lymphoma with combination chemotherapy, radiation and hematopoietic stem cell transplantation, a significant fraction of patients will not respond to treatment or will subsequently relapse and succumb to Hodgkin's lymphoma (HL). We have focused on CD25, the IL-2 receptor alpha subunit, as a target for systemic radioimmunotherapy of HL. The scientific basis for this choice is that with the exception of T regs, CD25 is not expressed by normal resting lymphoid cells whereas it is expressed on both a minority of Reed-Sternberg cells and also on regulatory T cells rosetting around the Reed-Sternberg cells. We have utilized the humanized monoclonal antibody, daclizumab that targets CD25 (IL-2R alpha) armed with yttrium-90 a radionuclide that provides strong beta emissions that kill tumor cells at a distance via a crossfire effect. Patients with histologically confirmed HL and expression of CD25 in at least 10% of the cells in the lymphomatous mass were eligible. Thirty consecutive patients with HL were entered. The patients had received a median of 4 prior chemotherapy regimens and were required to have had an autologous and/or allogeneic stem cell transplant or had refused a transplant. Patients were treated with an initial dose of 10 or 15 mCi of 90Y-daclizumab depending on transplant status. After the first cycle, patients could receive 90Y-daclizumab 15 mCi per cycle every 6 to 10 weeks to complete up to a maximum of 7 doses if tolerated. A total of 98 cycles of treatment were administered to 30 patients with a median aggregate radiation dose of 40 mCi. In 30 HL patients treated with 90Y-daclizumab there were 7 partial responses and 12 complete responses. Toxicities were limited to transient bone marrow suppression and the myelodysplastic syndrome (3 cases). Responses were seen among the 5 patients whose Reed-Sternberg cells expressed CD25 as well as in those whose neoplastic cells were CD25 negative provided that the associated rosetting T regs expressed CD25. The increased efficacy compared to alternative radioimmunotherapy strategies for HL appears to reflect the increase in the target antigen, CD25, in lymphomatous masses provided by the overexpression of CD25 by associated rosetting T cells, and the use of a high energy, beta-emitting radionuclide Yttrium-90 to arm the antibody that thereby does not have to come in contact with each tumor cell but can kill cells by crossfire at a distance. In conclusion, repeated 90Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3706.3706
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 4
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    90 Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma
    Proceedings of the National Academy of Sciences ; 2015
    In:  Proceedings of the National Academy of Sciences Vol. 112, No. 42 ( 2015-10-20), p. 13045-13050
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 112, No. 42 ( 2015-10-20), p. 13045-13050
    Abstract: Despite significant advances in the treatment of Hodgkin’s lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed–Sternberg cells and by most polyclonal T cells rosetting around Reed–Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody 90 Y-daclizumab. 90 Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with 90 Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed–Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25 − provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated 90 Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed–Sternberg cells provided meaningful therapy for select HL patients.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1516107112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2015
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
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    EBV-Related Lymphoproliferative Disease Complicating Therapy with the Anti-CD2 Monoclonal Antibody, Siplizumab, in Patients with T-Cell Malignancies
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 7 ( 2009-04-01), p. 2514-2522
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2009-04-01), p. 2514-2522
    Abstract: Purpose: We report an increased incidence of EBV-induced B-cell lymphoproliferative disease (LPD) in patients treated with siplizumab, an anti-CD2 antibody. The development of EBV-LPD has been associated with the use of immunosuppressive agents used in solid organ, bone marrow, and stem cell transplantation and in certain congenital immunodeficiencies. Experimental Design: We conducted a single-institution phase I dose-escalation trial of siplizumab, a humanized monoclonal antibody to CD2, in 29 patients with T-cell malignancies. Results: Although initial responses were encouraging, 4 (13.7%) patients developed EBV-LPD and the trial was stopped. Reductions in CD4+ and CD8+ cell count numbers in response to therapy were seen in all patients, but in those patients developing EBV-LPD a significantly greater reduction in natural killer (NK) cell number and CD2 expression on T cells was seen. These findings highlight the importance of NK-cell depletion and CD2 expression in addition to T-cell depletion in the etiology of EBV-LPD. Conclusions: The emergence of EBV-LPD may be associated with the ability of siplizumab to deplete both T and NK cells without affecting B cells. Agents that deplete T- and NK-cell populations without affecting B cell number should be screened for this potentially serious adverse event.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-1254
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
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    A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy
    American Association for Cancer Research (AACR) ; 2007
    In:  Clinical Cancer Research Vol. 13, No. 3 ( 2007-02-01), p. 958-964
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 13, No. 3 ( 2007-02-01), p. 958-964
    Abstract: Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points. Experimental Design: Three patients with colon cancer, four with non–Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25 +CD62L + declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. Conclusions: Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-1974
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
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  • 7
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    Alemtuzumab (Campath 1-H) in Patients with HTLV-1 Associated Adult T-Cell Leukemia/Lymphoma.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2010-2010
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2010-2010
    Abstract: This study investigated the antitumor activity of alemtuzumab (Campath 1-H) with regard to response rate, time to progression, overall survival and adverse events in patients with human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/ lymphoma (ATL). In a single institution non-randomized open-label phase II trial, 24 patients with chronic (n=2), acute (n=13) and lymphomatous (n=9) ATL were treated with intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Patients received antimicrobial prophylaxis from the initiation of treatment continuing for a minimum of 2 months after treatment, or until the peripheral blood CD4+ T-cells were ≥ 200 cells/μL. Tumor responses were assessed at the end of 4, 8, and 12 weeks. All patients were evaluable for toxicity and one patient was not evaluable for response due to early withdrawal. The overall objective response rate was 10 out of 23 patients (95% CI: 23 to 66%). Based on the 10 patients who responded, median time to response was 1.1 months (range, 1.0 to 3.0 months). The median response duration was 3.9 months. Median progression free survival of patients with chronic subtype was 2.0 months, 1.0 month for lymphomatous subtype and 2.4 months for acute subtype. Median time to treatment failure was 1.7 months. At data cut-off, (April 24, 2008), 6 (25%) patients were alive. Overall median survival was 5.9 months. Median overall survival by subtypes was 3.9 months for chronic, 4.8 months for lymphomatous, and 7.6 months for acute. Median survival for all responders from on study date was 8.4 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion and were generally grade 1 or 2, occurring mainly in the first week of alemtuzumab administration. All patients developed CMV antigenemia; however, only 3 (12.5%) were symptomatic. Grade 3 or 4 infections were reported in 6 (25%) patients. Median time to recovery of ALC to & gt;200 cells/μL was 1.9 months.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2010.2010
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 8
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    Online Resource
    EBV-Related Lymphoproliferative Disease Complicating Therapy with Siplizumab, a Novel Anti-CD2 Mediated T- and NK-Cell Depleting Agent, in Patients with T-Cell Malignancies.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 3565-3565
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3565-3565
    Abstract: Epstein Barr virus (EBV) has the capacity to transform B lymphocytes and in the setting of immunosuppression increases the risk of developing EBV induced lymphoproliferative disease (EBV LPD). This is a heterogeneous condition ranging from a benign polyclonal B cell proliferation to frank non-Hodgkin’s lymphoma. EBV LPD is associated with immunosuppressive agents used in solid organ, bone marrow and stem cell transplantation, and in certain congenital immunodeficiencies. We conducted a single institution phase I dose escalation study of siplizumab, a humanized monoclonal antibody to CD2, in patients with T-cell malignancies. A total of 29 patients (pts) were enrolled, of which 4 (13.7%) developed EBV LPD. In the original trial design (n=23) pts received escalating drug doses over 2 or 3 consecutive days per treatment week every 2 weeks (cohorts 1–7). In an attempt to increase the rate of drug delivery the trial was amended, for pts (n=6) to receive a single dose on day 0 and 14, and then once weekly thereafter (cohorts 8–10). While initial responses were exciting (2 complete responses, 7 partial responses and 10 stable disease) the development of EBV LPD was a concern. One of 23 (4.3%) pts in the original design and 3 of 6 (50%) in the revised schema developed EBV LPD within 6 months of starting therapy. The 29 pts included adult T-cell leukemia/lymphoma (n=15), large granular lymphocyte leukemia (n=7), cutaneous T-cell lymphoma (n=4) and peripheral T-cell lymphoma (n=3). A median of 2 (range 0–6) prior therapies and a median of 4 (range 1–26) courses of siplizumab with doses ranging from 0.4mg/kg to 4.8mg/kg were administered either biweekly or weekly depending on the cohort. Of the 4 EBV LPD cases, one responded to withdrawal of siplizumab, one to rituximab, another to combination chemotherapy and rituximab, and the remaining patient succumbed to a combination of her underlying disease and EBV-LPD. Review of T-cell trends in response to therapy demonstrated a reduction in the geometric mean of CD4 (84.9%, p & lt;0.001) and CD8 T-cell counts (91.5%, p & lt;0.001) between baseline and a timepoint after administration of the second cycle. There was no statistically significant difference in the degree of reduction between the two trial designs or those pts who developed EBV LPD. However, a statistically significant greater reduction in CD2 expression was seen in pts treated on the weekly schema (p=0.007) rather than biweekly and in those who developed EBV LPD (p=0.05) rather than those who did not. There was also a statistically significant greater reduction in NK cell number (p=0.04) with 2 treatment cycles from baseline in patients developing EBV LPD. These findings highlight the importance not only of T-cell depletion in the aetiology of EBV LPD but also NK cell depletion and reduction in CD2 expression on lymphocytes. The emergence of B-cell malignancy may be associated with the ability of siplizumab to deplete both T and NK cell number, without B-cell depletion. This toxicity should be screened for in other agents that deplete T cells without affecting B cell number.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.3565.3565
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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    detail.hit.zdb_id: 80069-7
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  • 9
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    Phase I Trial of Siplizumab in CD2-Positive Lymphoproliferative Disease.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 3353-3353
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 3353-3353
    Abstract: Siplizumab is a humanized IgG1κ class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells. In an animal model of adult T-cell leukemia/lymphoma (ATL), fifty percent of animals survived tumor challenge with 4 weeks of siplizumab treatment and the life-span of tumor bearing animals treated for six months was equivalent to that of animals not challenged with tumors. A single-center phase I dose escalation trial to assess maximum tolerated dose (MTD) and safety in patients (pts) with CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocyte leukemia (LGL) is ongoing. Eligibility includes Karnofsky performance status ≥70%; life expectancy & gt;2 months; appropriate hematological status and normal organ function; prior treatment with chemotherapy and monoclonal antibodies is allowed. Cohorts of 3 pts each receive escalating i.v. doses of siplizumab ranging from 0.4 to 4.8 mg/kg administered over 2–3 days per treatment week every other week for 16 weeks or until unacceptable toxicity or disease progression (PD). 16 pts have been enrolled into 5 cohorts: 0.4 (3 pts), 0.6 (3 pts), 0.8 (3 pts), 1.2 (4 pts) and 2.4 (3 pts) mg/kg per week with planned dose escalation to 3.4 and 4.8 mg/kg. Median number of courses received is 4 (range 1–8). Diagnoses include ATL (9), LGL (4), PTCL (1) and CTCL (2). Grade 1/2 infusional reactions primarily manifested as fever and chills were confined to the first dose of treatment in the majority of patients. Meperidine pretreatment significantly ameliorated infusional reactions. The median (range) percentage decrease in CD4, CD8, NK and malignant cell numbers in peripheral blood from baseline are 98(71–100%), 93(50–100%), 89(55–96%) and 88 (0–100%), respectively. No DLTs have occurred at this time. To date, 3 confirmed PRs have been observed (2 ATL, 1 LGL), 6 pts had stable disease, and 7 pts had PD. 1 pt discontinued therapy due to a siplizumab-related adverse event of polymyalgia rheumatica and 3 pts (2 ATL, 1 LGL) were removed due to CMV antigenemia (which was an off-treatment criterion at the time of study drug discontinuation). 4 patients have died during the one-year follow up period due to PD and 4 patients have completed all 8 courses of treatment. In conclusion-siplizumab has been well tolerated in this trial and the maximum tolerated dose has not been reached. The protocol has been amended to allow for treatment of CMV antigen positive patients provided oral antivirals are effective in preventing CMV disease and rising CMV levels. Anti-tumor activity has been observed in some patients. Enrollment in this study continues.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.3353.3353
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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    detail.hit.zdb_id: 80069-7
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