Regulation of CD23 isoforms on B-chronic lymphocytic leukemia

Goller, Martin; Kneitz, Christian; C, Mehringer; Müller, Karin; Jelley-Gibbs, Dawn M.; Gosselin, Edmund J.; Wilhelm, Martin; Tony, Hans Peter

doi:10.1016/s0145-2126(02)00007-3

Cited by 15 publications

(15 citation statements)

References 26 publications

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“…CD23 has been implicated in normal B-cell proliferation and survival, 33 and although CD23-deficient mice have normal B-cell development, indicating that the elimination of CD23 ϩ cells may not compromise the normal B-cell compartment, 34 we carefully evaluated the effects of CD23.CARspecific T cells on normal B lymphocytes. These cells can indeed express CD23, 28 especially as IgM-and IgD-positive B cells in the mantle zone of the secondary follicle, and, as illustrated in our experiments, they can circulate in the peripheral blood of healthy individuals. However, their expression of CD23 is low and, accordingly, we did not detect significant CD23.CAR-mediated cytolytic activity against these cells.…”

Section: Discussionsupporting

confidence: 69%

“…28 Whereas the percentages of double-positive CD19/CD23 cells were comparable in healthy donors and CLL patients at levels Ն 90% (n ϭ 5 and n ϭ 7, respectively; data not shown), as expected, 28,29 the level of expression of CD23 antigen was higher in CD19 ϩ CLL cells, when assessed as mean fluorescence intensity (MFI) (average MFI, 507, range 356-704; n ϭ 7, for CD19 ϩ CLL cells; average MFI, 183, range 97-273; n ϭ 5, for normal CD19 ϩ B lymphocytes; P Յ .005; Figure 3A). We then analyzed the cytotoxic effects of either CD23.CAR ϩ or CD19.CAR ϩ T lymphocytes against normal B lymphocytes.…”

Section: Cd23car ؉ T Lymphocytes Do Not Show Cytotoxic Activity Agaimentioning

confidence: 99%

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In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

Attianese

Marin

Hoyos

et al. 2011

Blood

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Chronic lymphocytic leukemia (CLL) is IntroductionChronic lymphocytic leukemia (CLL), the most common form of leukemia in adults in Western countries, 1 remains an incurable disease despite the development of new therapeutic regimens. 2,3 Allogeneic hematopoietic stem cell transplantation can be curative, but its application is limited to young adults, who represent a small percentage of patients with CLL. 2,4 Antibodies directed against different surface antigens are currently used in patients with CLL. 3 Although anti-CD52 (Campath-1) antibodies rapidly reduce the leukemic burden in the peripheral blood, they have limited biodistribution to secondary lymphoid organs, where CLL cells tend to accumulate. 5 In the case of anti-CD20 antibodies, the low levels of the antigen on leukemic B cells limit their use as a single agent in this disease. In addition, antibodies do not lead to long-term control of the disease because they do not establish an active memory immune response. 6 CLL is also susceptible to cell-mediated immune control, as indicated by the graft-versusleukemia effect associated with allogeneic hematopoietic stem cell transplantation, 7 and by the immune responses elicited in patients receiving leukemia-tumor vaccines. 8,9 Adoptive transfer of T lymphocytes genetically modified to express a chimeric antigen receptor (CAR) can combine the beneficial effects of both antibody-and T-cell-mediated immune responses. CARs are chimeric molecules that contain an extracellular binding moiety derived from an mAb (single-chain variable fragment [scFv]) coupled to an intracellular signaling moiety (usually the chain of the T-cell receptor complex). 6,10,11 When expressed by T lymphocytes, CARs can trigger T-cell activation and perforin/granzyme-B release 12 upon binding with the antigen expressed by tumor cells in a non-MHC-restricted manner, thus avoiding an important mechanism of tumor immune escape represented by the down-regulation of MHC molecules by tumor cells. 6 Adoptive transfer of CAR-transduced T lymphocytes may offer several advantages compared with the passive administration of antibodies, because T cells have enhanced tissue biodistribution and may establish a long-lasting antitumor immune response. 6 CARs targeting either CD19 or CD20 antigens have been developed to treat human B-cell-derived malignancies, [13][14][15] and clinical trials using these chimeric molecules are currently ongoing in several institutions. However, a potential major disadvantage of this strategy is that both CD19 and CD20 are expressed not only by leukemic cells, but also by normal B lymphocytes, and therefore the sustained elimination of these cells by CAR-modified T cells could result in a severe impairment of the humoral immunity, exacerbating the characteristic immunodeficiency present in patients with CLL. 16 Because of the importance of preserving the normal B cell compartment, the generation of CARs targeting antigens with a more restricted expression in tumor cells may have clinical relevance. 17 CD23 antigen repre...

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Section: Discussionsupporting

confidence: 69%

Section: Cd23car ؉ T Lymphocytes Do Not Show Cytotoxic Activity Agaimentioning

confidence: 99%

In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

Attianese

Marin

Hoyos

et al. 2011

Blood

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“…Indeed, when those patients in advanced B-CLL disease stages were sub-analysed, those with a lower percentage of CD23 expression had significantly shorter survival times. This is contrary to the suggestion that advanced disease is associated with higher levels of CD23 expression, based on the measurement of elevated serum levels of soluble cleaved CD23 molecules using ELISA techniques [17,23,24,38], these soluble CD23 molecules (sCD23) resulting from the spontaneous proteolysis, cleavage and release of one of the two isoforms of the trans-membrane CD23 molecule [39].…”

Section: Discussionmentioning

confidence: 73%

Analysis of CD23 antigen expression in B-chronic lymphocytic leukaemia and its correlation with clinical parameters

Jurišić

Čolović²,

Kraguljac³

et al. 2008

Med Oncol

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B-Chronic lymphocytic leukaemia (B-CLL) is a monoclonal malignancy characterized by an accumulation of terminally differentiated small and anergic B lymphocytes in the blood, bone marrow and other tissues. CD23 antigen, a trans-membrane glycoprotein, promotes the activation and proliferation of normal B lymphocytes and has an important role in the process of malignant transformation in B-CLL. This retrospective cohort study of 77 consecutive newly diagnosed B-CLL patients, 43 males, 34 females, median age of 62 years, examined CD23 expression and correlations with clinical parameters. CD23+ was negatively correlated with pro-lymphocyte infiltration of the bone marrow (P<0.01) and peripheral blood lymphocyte counts (P<0.001). Lower CD23 expression was correlated with lower serum immunoglobulin levels (P<0.05), especially IgG; while greater CD23 expression was positively correlated with higher CD5 levels. B-CLL patients with a percentage of CD23+ lymphocytes >40% had longer survival (92.8 months) than those expressing <40% (35.3 months) (P=0.001). CD23 is not uniformly expressed by lymphocytes in B-CLL patients, and the differences in expression are dependent on a number of clinical parameters, including the peripheral blood lymphocyte count and the degree of pro-lymphocyte infiltration of the bone marrow. CD23 expression is significantly decreased in patients with extremely high lymphocyte counts (PBL counts of >100 x 10(9)/l) and in the advanced stages of disease.

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“…Binding of mAb to CD23 induce ADCC, CDC and apoptosis [48,49]. Its soluble form -sCD23, generated as a result of proteolytic cleavage is released to the blood [51]. CD23, a trans-membrane glycoprotein is expressed on normal mature B-lymphocytes as well as on most CLL cells [50].…”

Section: Lumiliximab (Idec-152)mentioning

confidence: 99%

Potential New Agents for Chronic Lymphocytic Leukemia Treatment

Kiliańska

Rogalińska²

2010

ACAMC

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Chronic lymphocytic leukemia (CLL) is the most frequent type of hematological cancer in the Western World. An accumulation of leukemic cells in peripheral blood of patients is a result of apoptosis disturbances as well as an increase in germinal centers CLL cell proliferation. The differences between CLL patients in the course and response to therapy reflects personal variability between patients in their genetic material. It was documented that many sufferers from CLL are over 60 years old, and because of many countries' population obsolescence this type of leukemia could become more frequent in the future. CLL remains incurable, and the therapy regimens available at present could induce even complete remissions, but finally a relapse of the disease. The etiology of this disease is still not known, but our understanding of the processes running in CLL cells has significantly increased. A number of new agents with potential of CLL cell elimination by apoptosis or autophagy were characterized. Some of them reflect potential in cell sensitization to standard therapy. The major challenge for the future is to develop targeted anti-cancer therapy and design the optimal personalized manner of CLL treatment. A special interest is focused on anti-cancer agents - natural substances of plant origin. This paper reviews chosen new anti-leukemic agents belonging to different drug-classes (new monoclonal antibodies or apoptosis-, BCR signaling- and cell cycle-related inhibitors, substances of plant origin) which are under intense investigation in preclinical studies and early clinical trials.

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Regulation of CD23 isoforms on B-chronic lymphocytic leukemia

Cited by 15 publications

References 26 publications

In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor

Analysis of CD23 antigen expression in B-chronic lymphocytic leukaemia and its correlation with clinical parameters

Potential New Agents for Chronic Lymphocytic Leukemia Treatment

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