Jump-starting the T cells in CLL

Blood ◽  
2013 ◽  
Vol 121 (20) ◽  
pp. 4016-4017 ◽  
Author(s):  
James B. Johnston
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Immune Synapse

In this issue of Blood, Shanafelt and colleagues demonstrate that T-cell immune synapse function can be increased in chronic lymphocytic leukemia (CLL), both by reducing tumor burden with immunochemotherapy and by lenalidomide.1

Preclinical Analyses Support Clinical Investigation of Combined Anti-CD19 CAR-T Cell, JCAR017 with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3231-3231 ◽  
Author(s):  
Jim Qin ◽  
Alex Baturevych ◽  
Sherri Mudri ◽  
Ruth Salmon ◽  
Michael Ports
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Initial Growth ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Chronic lymphocytic leukemia (CLL) drives systemic immune suppression and T cell dysfunction in patients, highlighting an important consideration in this setting for the manufacturing and efficacy of adoptive cell therapies using autologous T cells. In clinical studies, anti-CD19 CAR-T cells produce durable and complete responses in leukemic and some lymphomatous B cell malignancies. While preconditioning with cyclophosphamide (Cy) and fludarabine (Flu) has improved CAR-T responses in CLL patients, reported complete response rates still have been below 50%; additional therapeutic strategies likely will be required. Ibrutinib, an irreversible inhibitor of BTK, has been approved as a frontline treatment option for patients with CLL. The potent off-BTK activity of ibrutinib on ITK and TEC family kinases could affect CAR T cell biology. Recent work highlighted the ability of ibrutinib to restore CLL patient T cell functionality, enhance CAR-T production and potentially improve clinical efficacy. Additional preclinical work demonstrated improved tumor clearance when anti-CD19 CAR T cells were combined with ibrutinib in several murine tumor models. A preclinical evaluation of the combination between the anti-CD19 CAR-T product, JCAR017, and ibrutinib was performed to determine feasibility for clinical use in CLL. JCAR017 is a second generation CAR-T cell product candidate that contains a 41BB costimulatory endo-domain and is currently in phase 1 trials for non-Hodgkin lymphoma (NHL). A series of in vitro studies assessed the functional activity of JCAR017 cells (derived from 3 healthy donors), in combination with ibrutinib (500-0.05nM), across a dose range covering the cMax and cMin. Cytolytic activity was monitored by co-culturing CAR-T cells with ibrutinib-resistant K562 CD19 tumor cells at an effector-to-target ratio of 2.5:1. Ibrutinib, at concentrations tested, did not inhibit the cytolytic function of JCAR017 cells. For cells derived from some donors, addition of ibrutinib appeared to increase % target killing. To address ibrutinib effects on JCAR017 activation, cell surface markers and cytokines were tracked over 4 days following stimulation with irradiated K562 CD19 cells. We observed no significant effect on JCAR017 surface expression of CD25, CD38, CD39, CD95, CD62L, CCR7, or CD45RO, or of EGFRt, a surrogate transduction marker. With addition of ibrutinib, we observed a modest decrease in the percentage of cells expressing CD69, CD107a and PD-1. With 5 and 50nM of ibrutinib, there was a 19.5% (p<0.01) average increase in IFNγ production. At supraphysiological concentrations (500nM) we observed a 20% (p<0.05) decrease in IL-2 production, suggesting ibrutinib at high concentrations may dampen T cell activation. CAR-T cell expansion after repeated antigen stimulation has been shown to be a predictor of in vivo efficacy. JCAR017 cells stimulated every 3-4 days with irradiated target cells in the presence of ibrutinib showed no inhibition of initial growth. However, after 5 rounds of stimulation, JCAR017 + ibrutinib cells from 1 donor had enhanced proliferation compared to control, untreated cells (p<0.05). Interestingly, after 5 rounds of serial stimulation, we observed an increased proportion of CD4+CXCR3+CRTh2- Th1 cells with 500nM ibrutinib treatment compared to control (p<0.01). We assessed the in vivo anti-tumor activity of JCAR017 in combination with ibrutinib using NSG mice injected with 5x105 Nalm6-luciferase cells. After tumor engraftment, a suboptimal dose (5x105) of JCAR017 cells was transferred to mice and ibrutinib (25 mg/kg qd) was administered for the duration of the study. Ibrutinib treatment alone had no effect on tumor burden compared to vehicle treatment. Mice treated with a suboptimal JCAR017 dose + ibrutinib showed decreased tumor burden (p<0.05) and increased median survival from 44 days to >80 days (p<0.001) compared to the group receiving the suboptimal JCAR017 dose + vehicle. Similar effects were seen in replicate studies using JCAR017 cells produced from multiple donors. Ex vivo evaluation for CAR-T quantitation and immunophenotyping was also performed. Taken together, the results suggest that ibrutinib enhances intrinsic JCAR017 activity and may improve outcomes in CLL patients treated with anti-CD19 CAR T therapy, irrespective of BTK mutational status. A Phase 1b study of JCAR017 in combination with ibrutinib for BTKi R/R CLL is planned. Disclosures Qin: Juno Therapeutics: Employment. Baturevych:Juno Therapeutics: Employment. Mudri:Juno Therapeutics: Employment, Equity Ownership. Salmon:Juno Therapeutics: Employment. Ports:Juno Therapeutics: Employment.

scholarly journals Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia

2020 ◽  
Vol 8 (1) ◽  
pp. e000471 ◽  
Author(s):  
Veronika Mancikova ◽  
Helena Peschelova ◽  
Veronika Kozlova ◽  
Aneta Ledererova ◽  
Adriana Ladungova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Burden ◽  
Lymphocytic Leukemia ◽  
Car T Cells ◽  
Cell Engraftment ◽  
Car T

BackgroundWhile achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy.MethodsFirst, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9ATM-mutated, 8TP53-mutated, and 9 without mutations inATM,TP53,NOTCH1orSF3B1) and 6IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by ‘2S stimulation’ through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generatedATM-knockout andTP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT),ATM-knockout orTP53-knockout cells was also performed.ResultsPrimary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. ‘2S’ stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells’ in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-γ when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells’ survival. In vivo, CAR T cells prolonged the survival of mice injected with WT,TP53-knockout andATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared withATM-knockout,TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012).ConclusionsWhile in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated withTP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

scholarly journals Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer

Blood ◽  
2012 ◽  
Vol 120 (7) ◽  
pp. 1412-1421 ◽  
Author(s):  
Alan G. Ramsay ◽  
Andrew J. Clear ◽  
Rewas Fatah ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Immune Evasion ◽  
Actin Polymerization ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Lymphocytic Leukemia ◽  
Functional Screening ◽  
Immunologic Synapse

Abstract Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand–induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell–inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer.

Evaluation of vecabrutinib as a model for non-covalent BTK/ITK inhibition for treatment of chronic lymphocytic leukemia

Blood ◽  
2021 ◽  
Author(s):  
Billy Michael Chelliah Jebaraj ◽  
Annika Müller ◽  
Rashmi Priyadharshini Dheenadayalan ◽  
Sascha Endres ◽  
Philipp M. Roessner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Inhibitory Effect ◽  
Lymphocytic Leukemia ◽  
Transfer Model ◽  
Treatment Benefit ◽  
Btk Inhibitors

Covalent Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have proven to be highly beneficial in the treatment of chronic lymphocytic leukemia (CLL). Interestingly, the off-target inhibition of IL-2-inducible T-cell kinase (ITK) by ibrutinib may also play a role in modulating the tumor microenvironment, potentially enhancing the treatment benefit. However, resistance to covalently binding BTK inhibitors can develop by a mutation in cysteine 481 of BTK (C481S), which prevents the irreversible binding of the drugs. In the present study we performed pre-clinical characterization of vecabrutinib, a next generation non-covalent BTK inhibitor, with ITK inhibitory properties similar to those of ibrutinib. Unlike ibrutinib and other covalent BTK inhibitors, vecabrutinib showed retention of the inhibitory effect on C481S BTK mutants in vitro, similar to that of wildtype BTK. In the murine Eµ-TCL1 adoptive transfer model, vecabrutinib reduced tumor burden and significantly improved survival. Vecabrutinib treatment led to a decrease in CD8+ effector and memory T-cell populations, while the naïve populations were increased. Of importance, vecabrutinib treatment significantly reduced frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike ibrutinib, vecabrutinib treatment showed minimal adverse impact on activation and proliferation of isolated T-cells. Lastly, combination treatment of vecabrutinib with venetoclax was found to augment treatment efficacy, significantly improve survival and lead to favourable reprogramming of the microenvironment in the murine Eµ-TCL1 model. Thus, non-covalent BTK/ITK inhibitors such as vecabrutinib may be efficacious in C481S BTK mutant CLL, while preserving the T-cell immunomodulatory function of ibrutinib.

scholarly journals Defective T cell-mediated, isotype-specific immunoglobulin regulation in B cell chronic lymphocytic leukemia

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1012-1020 ◽  
Author(s):  
JS Moore ◽  
MB Prystowsky ◽  
RG Hoover ◽  
EC Besa ◽  
PC Nowell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Specific Immunoglobulin ◽  
Cell Chronic Lymphocytic Leukemia

The consistent occurrence of T cell abnormalities in patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that the non- neoplastic host T cells may be involved in the pathogenesis of this B cell neoplasm. Because potential defects of immunoglobulin regulation are evident in B-CLL patients, we investigated one aspect of this by studying the T cell-mediated immunoglobulin isotype-specific immunoregulatory circuit in B-CLL. The existence of class-specific immunoglobulin regulatory mechanisms mediated by Fc receptor-bearing T cells (FcR + T) through soluble immunoglobulin binding factors (IgBFs) has been well established in many experimental systems. IgBFs can both suppress and enhance B cell activity in an isotype-specific manner. We investigated the apparently abnormal IgA regulation in a B-CLL patient (CLL249) whose B cells secrete primarily IgA in vitro. Enumeration of FcR + T cells showed a disproportionate increase in IgA FcR + T cells in the peripheral blood of this patient. Our studies showed that the neoplastic B cells were not intrinsically unresponsive to the suppressing component of IgABF produced from normal T cells, but rather the IgABF produced by the CLL249 host T cells was defective. CLL249 IgABF was unable to suppress IgA secretion by host or normal B cells and enhanced the in vitro proliferation of the host B cells. Size fractionation of both normal and CLL249 IgABF by gel-filtration high- performance liquid chromatography (HPLC) demonstrated differences in the ultraviolet-absorbing components of IgABF obtained from normal T cells v that from our patient with defective IgA regulation. Such T cell dysfunction may not be restricted to IgA regulation, since we have found similar expansion of isotype-specific FcR + T cells associated with expansion of the corresponding B cell clone in other patients with B-CLL. These data suggest that this T cell-mediated regulatory circuit could be significantly involved in the pathogenesis of B-CLL.

scholarly journals Defective interleukin-2 production and responsiveness by T cells in patients with chronic lymphocytic leukemia of B cell variety

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 279-284 ◽  
Author(s):  
O Ayanlar-Batuman ◽  
E Ebert ◽  
SP Hauptman
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Proliferative Response ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
T Cell Proliferation ◽  
Activated T Cells

Abstract The present studies were designed to investigate the mechanism(s) of the defective T cell proliferative response to various stimuli in patients with B cell chronic lymphocytic leukemia B-CLL. In 14 patients with advanced B-CLL (stage III or IV) we found the T cell response in the autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR) to be 35.7% and 30% of the controls, respectively. Proliferation in the MLR depends upon the production of and response to interleukin 2 (IL 2), a T cell growth factor. IL 2 production in eight B-CLL patients was 22% of the control. The response to IL 2 was measured by the increase in the T cell proliferation in the MLR with the addition of IL 2. T cell proliferation in both the auto and allo MLR of CLL patients was significantly lower than in the controls after the addition of IL 2. The proliferative response of normal T cells to stimulation by CLL B cells was 50% of the control. This latter response was increased to control levels when cultures were supplemented with exogenous IL 2, suggesting that CLL B cells could stimulate IL 2 receptor generation in normal T cells in an allo MLR, but not IL 2 production. The presence of IL 2 receptors on activated T cells was directly determined using anti- Tac, a monoclonal antibody with specificity for the IL 2 receptor. Of the mitogen- or MLR-activated T cells in CLL patients, 6% and 10%, respectively, expressed Tac antigen, whereas identically stimulated control T cells were 60% and 47% Tac+, respectively. Our findings suggest that T cells in B-CLL are defective in their recognition of self or foreign major histocompatibility antigens as demonstrated by their impaired responsiveness in the MLR. Thus, these cells are unable to produce IL 2 or generate IL 2 receptors.

CD40-Activated B-Cell Chronic Lymphocytic Leukemia Cells for Tumor Immunotherapy: Stimulation of Allogeneic Versus Autologous T Cells Generates Different Types of Effector Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1992-2002 ◽  
Author(s):  
Raymund Buhmann ◽  
Annette Nolte ◽  
Doreen Westhaus ◽  
Bertold Emmerich ◽  
Michael Hallek
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Tumor Antigens ◽  
Lymphocytic Leukemia ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Stimulation Of

Although spontaneous remissions may rarely occur in B-cell chronic lymphocytic leukemia (B-CLL), T cells do generally not develop a clinically significant response against B-CLL cells. Because this T-cell anergy against B-CLL cells may be caused by the inability of B-CLL cells to present tumor-antigens efficiently, we examined the possibility of upregulating critical costimulatory (B7-1 and B7-2) and adhesion molecules (ICAM-1 and LFA-3) on B-CLL cells to improve antigen presentation. The stimulation of B-CLL cells via CD40 by culture on CD40L expressing feeder cells induced a strong upregulation of costimulatory and adhesion molecules and turned the B-CLL cells into efficient antigen-presenting cells (APCs). CD40-activated B-CLL (CD40-CLL) cells stimulated the proliferation of both CD4+ and CD8+ T cells. Interestingly, stimulation of allogeneic versus autologous T cells resulted in the expansion of different effector populations. Allogeneic CD40-CLL cells allowed for the expansion of specific CD8+cytolytic T cells (CTL). In marked contrast, autologous CD40-CLL cells did not induce a relevant CTL response, but rather stimulated a CD4+, Th1-like T-cell population that expressed high levels of CD40L and released interferon-γ in response to stimulation by CD40-CLL cells. Together, these results support the view that CD40 activation of B-CLL cells might reverse T-cell anergy against the neoplastic cell clone, although the character of the immune response depends on the major histocompatibility complex (MHC) background on which the CLL or tumor antigens are presented. These findings may have important implications for the design of cellular immunotherapies for B-CLL.

Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2519-2519 ◽  
Author(s):  
Chia-Huey Lin ◽  
Thomas Kerkau ◽  
Christine Guntermann ◽  
Martin Trischler ◽  
Niklas Beyersdorf ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activation Markers ◽  
Cell Chronic Lymphocytic Leukemia

Abstract B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955–66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917–2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients.

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