Humanization of an Anti-CCR4 Antibody That Kills Cutaneous T-Cell Lymphoma Cells and Abrogates Suppression by T-Regulatory Cells

Chang, De-Kuan; Sui, Jianhua; Geng, Shusheng; Muvaffak, Asli; Bai, Ming; Fuhlbrigge, Robert C.; Lo, Agnes S.; Yammanuru, Anuradha; Hubbard, Luke; Sheehan, Jared; Campbell, James J.; Zhu, Quan; Kupper, Thomas S.; Marasco, Wayne A.

doi:10.1158/1535-7163.mct-12-0278

Cited by 64 publications

(53 citation statements)

References 49 publications

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“…While CCR4 has been previously reported to be over-expressed in some haematological malignancies [11][12][13] and solid tumors with a high metastatic potential [14][15][16], others, in line with our results, showed that, in B-CLL cells, CCR4 expression may be absent or significantly reduced when compared to normal B cells from elderly donors [25]. Hence, one may quickly infer that CCR4 does not qualify as a reliable diagnostic or therapeutic target for B-CLL patients.…”

Section: Discussionsupporting

confidence: 75%

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Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia

Grigore¹,

Ivanov²,

Zlei³

et al. 2014

Romanian Review of Laboratory Medicine

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Traffic of tumor-and normal cells through the peripheral blood (PB) of patients with B-cell chronic lymphocytic leukemia (B-CLL) to the lymph nodes (LN) or spleen/ liver sites is governed by specific changes in CCR7, CXCR5, CXCR3, CCR4, CD3, CD4, CD8, CD27, CD28, CD45RA, CD25, CD127, CD38 was also report a significant increase in the frequency of total T cells and T cell subsets (effector-and central memory CD4+ T cells, regulatory T cells, follicular T helper cells, distinct functional CD8+ T cells) with the occurrence of specific clinical manifestations. Chemokine receptor expression on circulating CD4+ T cell subsets was augmented in connection to

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Section: Discussionsupporting

confidence: 75%

“…Data from the literature point to chemokine receptors as crucial players in the development and progression of lymphoid neoplasms [6,[10][11][12][13][14][15][16][17][18][19]. B-and T-cell circulation to LN has been proven to be strictly regulated by a combination of different chemokines (e.g.…”

Section: Discussionmentioning

confidence: 99%

Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia

Grigore¹,

Ivanov²,

Zlei³

et al. 2014

Romanian Review of Laboratory Medicine

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“…From a mechanistic point of view, CCR4 overexpression has been described specifically in transformed CTCL compared with nonmalignant cells, [43][44][45] and its inhibition can lead to CTCL cell death concomitant with suppression of Treg activity. 46 In contrast, different mutations affecting members of the NFkB pathway have been found in our analysis (such as TRAF6, RELB, or CARD11). It is well-known that NFkB activity regulates the expression of multiple key T-cell cytokines such as CCL17 and CCL22 (CCR4 ligands) or interleukin 4 (IL-4), IL-6, and IL10, which may confer survival advantages in an autocrine or paracrine manner through the activation of the JAK/STAT pathway, which was also a frequently mutated pathway in our series (Table 1; Figure 4).…”

Section: Discussionmentioning

confidence: 55%

PLCG1 mutations in cutaneous T-cell lymphomas

Vaqué

Gómez‐López

Monsálvez

et al. 2014

Blood

197

199

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Key Points• Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor kB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation. (Blood. 2014;123(13):2034-2043

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“…ATLL cells, like cutaneous T-cell lymphomas, express the chemokine receptor CCR4, which is involved in skin homing and is expressed at high levels in miscellaneous cutaneous T-cell lymphomas, including ATL, and also expressed by Treg cells, involved in suppressing autoimmunity, and which can suppress T-cell immune responses against neoplasms. The MoAbs, anti-CCR4, active against various cutaneous T-cell neoplasms, which express CCR4 (Chang et al, 2012) has also shown activity in patients with advanced ATLL. Studies of its use in addition to chemotherapy suggest that the antibody/chemotherapy regimen is more effective, but optimal therapy remains to be defined.…”

Section: Aggressive Ptclmentioning

confidence: 99%

Non‐Hodgkin Lymphomas

Magrath

2014

Encyclopedia of Life Sciences

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Non‐Hodgkin lymphomas (NHLs) are malignant neoplasms of lymphoid cells, the predominant cells of the immune system. This term encompasses lymphocytes and their precursor as well as their progeny cells and natural killer cells. The defining characteristics of NHLs are their gene and microribonucleic acid (miRNA) expression patterns, which differ for each lymphoma subtype and also from those of closely related normal cell types. This is a consequence of a broad range of genetic changes – including gross changes at chromosomal level, namely translocations, whole or partial chromosome losses and other, smaller changes in individual genes ranging from point mutations to deletions that result in modifications of the molecular pathways of cells that cause corresponding modifications in cell behaviour. The genetic changes that give rise directly to NHLs are induced by physical, chemical or biological environmental agents (rarely, genetic changes that predispose to lymphomas may be inherited or present from birth) or the presence of viral sequences capable of modifying normal gene expression pattern and/or molecular pathways in the relevant cell type. At the clinical level, the behaviour of malignant lymphomas varies from indolent to aggressive. Lymphomas may be observed, treated with chemotherapy or with various combinations of chemotherapy, radiation and occasionally surgery (e.g. splenectomy). Key Concepts: NHLs are malignant neoplasms that arise from lymphoid cells, the predominant cells of the immune system, which include lymphocytes and their precursor and progeny cells. The immediate cause of lymphomas is genetic change, often chromosomal aberrations such as translocations, but this may be predisposed to by infections, particularly those that influence immunoregulation. Clinical distinctions such as nodal and extranodal lymphomas or bone marrow involvement, once the primary means of identifying diseases, do not have taxonomic significance (i.e. they are not, in themselves, indicators of a different disease). Mature lymphoid cells express an antigen‐binding receptor that is the external starting point of a major signalling pathway extending to the cell nucleus that is critical to lymphoid cell proliferation; mutations in this signalling pathway may simulate tonic expression of the TCR or BCR, even if the latter are normal, therefore, giving rise to inappropriate cell proliferation in the absence of antigen. The requirement of the adaptive immune system for antibodies to be able to bind tightly to antigen, which is achieved by selection of the antibody with the ‘best fit’ to antigen in the germinal follicle through a process of somatic mutation within the antibody variable region (see immune system and also class switching), a process mediated by activation‐induced cytidine deaminase, can result in significant structural rearrangements within the antibody molecule, including double‐strand breaks in the DNA. These processes, which have been shown to increase the risk of developing chromosomal translocations in mice, are probably relevant to the genesis of major cytogenetic changes in human lymphoid cells, some of which may be pertinent to lymphoma development. Some chronic infections and inflammatory processes cause activation of lymphoid cells, and predisposition to lymphoma development. Inherited (e.g. XLP) and acquired immunodeficiencies (e.g. HIV) may increase the risk of lymphoma development by modifying regulation of the immune system. Understanding the molecular mechanisms of lymphomagenesis as well as the molecular changes associated with lymphocyte differentiation can lead to targeted approaches to therapy, that is, the development of molecules which bind with high specificity to identified molecular targets, and either modify their actions or enable the introduction of a high local concentration of toxin or radionuclide, in either case producing a potentially therapeutic effect which is likely to be more specific and less toxic than conventional chemotherapy. When chronic infection leads to lymphoma, treatment of the underlying disease may induce complete remission and sometimes cure. In general, the more aggressive (rapidly progressive) lymphomas respond well to intensive therapy, and a proportion of such cases can be cured although recent research has suggested that some indolent lymphomas are also potentially curable by drugs that alter the microenvironment they require for survival.

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Humanization of an Anti-CCR4 Antibody That Kills Cutaneous T-Cell Lymphoma Cells and Abrogates Suppression by T-Regulatory Cells

Cited by 64 publications

References 49 publications

Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia

Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia

PLCG1 mutations in cutaneous T-cell lymphomas

Non‐Hodgkin Lymphomas

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