Receptor-Directed Therapy of T-Cell Leukemias and Lymphomas

Morris, John C.; Waldmann, Thomas A.; Janik, John E.

doi:10.1080/15476910802129661

Cited by 16 publications

(19 citation statements)

References 116 publications

(75 reference statements)

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“…ATL cells express CD2, CD4, CC chemokine receptor 4 (CCR4), CD52, 18 and high levels of CD25 (IL-2Ra) that can be targeted by various monoclonal antibodies. 19 Using our MET-1 murine model of human ATL, we demonstrated efficacy using anti-CD25 (daclizumab), anti-CD30 (HeFi), anti-CD2 (siplizumab), and anti-CD52 (alemtuzumab). This was paralleled by efficacy with these same antibodies in clinical trials in patients with ATL.…”

Section: Introductionmentioning

confidence: 96%

Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

Chen

Pise-Masison

Shih

et al. 2013

Blood

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• Markedly additive antitumor activity with the combination of a selective survivin suppressant (YM155) and alemtuzumab in adult T-cell leukemia.Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4 1 CD25 1 lymphocytes caused by human T-cell lymphotropic virus type 1. Currently, there is no accepted curative therapy for ATL. In gene expression profiling, the antiapoptotic protein survivin (BIRC5) demonstrated a striking increase in ATL, and its expression was increased in patient ATL cells resistant to the anti-CD52 monoclonal antibody alemtuzumab . In this study, we investigated the antitumor activity of a small-molecule survivin suppressant YM155 alone and in combination with alemtuzumab in a murine model of human ATL (MET-1). Both YM155 alone and its combination with alemtuzumab demonstrated therapeutic efficacy by lowering serum soluble IL-2Ra (sIL-2Ra) levels (P < .001) and prolonged the survival of tumor-bearing mice (P < .0001). Moreover, the combination of YM155 with alemtuzumab demonstrated markedly additive antitumor activity by significantly lowering serum sIL-2Ra levels and improving the survival of leukemia-bearing mice compared with monotherapy with either YM155 (P < .001) or alemtuzumab (P < .05). More significantly, all mice that received the combination therapy survived and were tumor free >6 months after treatment. Our data support a clinical trial of the combination of YM155 with alemtuzumab in ATL. This trial was registered at www.clinicaltrials.gov as #NCT00061048. (Blood. 2013;121(11):2029-2037 Introduction Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 1 CD25 1 T lymphocytes. 1 The etiologic agent of ATL is human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-I is a type C retrovirus that is endemic in Central and Southern Africa, southern Japan, the Caribbean basin, and northern South America.2 Less than 5% of individuals infected with HTLV-1 develop either ATL or a chronic inflammatory disease of the central nervous system, HTLV-1 associated myelopathy/tropical spastic paraparesis. The course of ATL is variable, and 4 clinical subtypes have been described: smoldering, chronic, lymphomatous, and acute.The treatment of the aggressive forms of ATL has been a challenge. The aggressive ATL subtypes are characterized by hypercalcemia, a large tumor burden with multiorgan failure, multidrug resistance, and frequent infectious complications due to a profound T-cell immunodeficiency. Leukemic cells from patients with ATL are often resistant to conventional chemotherapeutic agents as a result of the overexpression of the MDR gene and mutations of the p53 gene. 3,4 The overall survival of ATL patients is poor, with a median survival ranging from 5 to 13 months. Single agents such as the nucleoside analogs fludarabine, 5 pentostatin, 6 and cladribine 7 yield low response rates. Several combination chemotherapy regimens have been investigated, but none have demonstrated a survival advantage compared with standard cyclophosphamide...

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Section: Introductionmentioning

confidence: 96%

Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

Chen

Pise-Masison

Shih

et al. 2013

Blood

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“…Anti-CD2 treatment has been used in a mixed group of T cell malignancies where objective tumour responses were observed. However, a marked decline in CD4 + and CD8 + T cells and in natural killer (NK) cells resulted in CMV reactivation and development of EBV-related B-cell lymphoproliferative disease (Morris et al, 2008). Within the field of lymphoma, immunotherapy with anti-CD4 antibodies, including zanolimumab, has previously only been tested in CTCL (Knox et al, 1991(Knox et al, , 1996Kim et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of zanolimumab (HuMax‐CD4) in relapsed or refractory non‐cutaneous peripheral T cell lymphoma

et al. 2010

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SummaryThe efficacy and safety of zanolimumab (HuMax-CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty-one adult patients with relapsed or refractory CD4 + PTCL of noncutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCLnot otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a singlearm multi-centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26-85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III-IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL-NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor-prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.

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“…93 Finally, as for AL, therapeutic monoclonal antibodies are increasingly used in LPD, again not only directed to B cells but also in trials aimed at T-cell proliferations. 94 This document provides the consensus collective view of participants of the ELN WP10 group as to the numbers and characteristics of markers necessary for a proper diagnosis of hematological malignancies in flow cytometry. The relevance of each of the suggested markers has been outlined and referenced, and is summarized in Supplementary Table 5.…”

Section: Additional Useful Markersmentioning

confidence: 99%

Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10

et al. 2011

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The European LeukemiaNet (ELN), workpackage 10 (WP10) was designed to deal with diagnosis matters using morphology and immunophenotyping. This group aimed at establishing a consensus on the required reagents for proper immunophenotyping of acute leukemia and lymphoproliferative disorders. Animated discussions within WP10, together with the application of the Delphi method of proposals circulation, quickly led to post-consensual immunophenotyping panels for disorders on the ELN website. In this report, we established a comprehensive description of these panels, both mandatory and complementary, for both types of clinical conditions. The reason for using each marker, sustained by relevant literature information, is provided in detail. With the constant development of immunophenotyping techniques in flow cytometry and related software, this work aims at providing useful guidelines to perform the most pertinent exploration at diagnosis and for follow-up, with the best cost benefit in diseases, the treatment of which has a strong impact on health systems.

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Receptor-Directed Therapy of T-Cell Leukemias and Lymphomas

Cited by 16 publications

References 116 publications

Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

Markedly additive antitumor activity with the combination of a selective survivin suppressant YM155 and alemtuzumab in adult T-cell leukemia

Phase II trial of zanolimumab (HuMax‐CD4) in relapsed or refractory non‐cutaneous peripheral T cell lymphoma

Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10

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