Successful Treatment of Cutaneous Chronic Lymphocytic Leukemia with a Topical Toll Receptor 7/8 Antagonist (Imiquimod).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4832-4832
Author(s):  
Lisa Hicks ◽  
J. Mena ◽  
D. E. Spaner
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Surface Expression ◽  
Cytotoxic T Cell ◽  
First Case

Abstract Background: B cells express toll-like-receptor-7 (TLR7), a powerful modulator of inate immunity. We hypothesized that the immunogenicity of indolent B cell lymphomas and leukemias could be increased through activation of the TLR7 pathway. This might lead to increased immune clearance of malignant cells. Imiquimod 5% (an imidazoquinolone) has recently been identified as a TLR 7/8 agonist. It is available as a topical formulation and has demonstrated activity against condylomata as well as skin carcinomas. A small number of case reports also suggest activity against cutaneous T cell lymphoma. Case: A 71 year old Caucasian man presented with Rai Stage 0 CLL. For approximately 8 years prior to presentation, he suffered recurrent, erythematous, nodular lesions on his hands, arms and torso. The lesions were removed with liquid nitrogen but recurred. At the time of diagnosis with CLL, several lesions were present. Biopsy demonstrated a diffuse infiltrate of small round lymphocytes without epidermotropism. CD20 staining was positive. Molecular analysis confirmed a monoclonal B cell population consistent with B cell lymphoma. The patient was otherwise asymptomatic and did not warrant conventional therapy for CLL. Based on the safety and efficacy of imidazoquinoline in other skin cancers, he was offered and consented to a trial of this therapy. The drug was applied to the affected area 3x per week as recommended for treatment of genital warts. After 8 weeks, an area of hypopigmentation had formed, however the size of the lesion had not decreased. The frequency of application was increased to 1x per day. Over a 6 week period the lesion gradually disappeared. Six months after stopping the drug, the lesion has not recurred. No side effects were noted. Untreated lymphomatous lesions and peripheral blood lymphocyte counts did not change over the course of treatment. In vitro Data: We hypothesized that Imiquimod might increase the immunogenicity of CLL cells by increasing their surface expression of costimulatory molecules. To investigate this hypothesis, the above patient’s CLL cells were isolated (with his consent) directly through negative selection and then incubated for 48h with an active soluble imidazoquinalone or with a control. Expression of co-stimulatory molecules was determined by flow cytometry pre and post-incubation. CD80, 83, 86 and 54 surface expression were found to be increased significantly by TLR-7 agonists in vitro. Conclusion: We report the first case of Imiquimod activity against a cutaneous B cell lymphoma. We propose that the drug increases co-stimulatory molecule expression by malignant B cells, thereby facilitating cytotoxic T cell activation and killing of CLL cells. We believe that further study of TLR7 agonists is warranted in B cell malignancies.

Primary T-Cell–Rich B-Cell Lymphoma Masquerading as a Meningioma

2000 ◽  
Vol 124 (11) ◽  
pp. 1700-1703
Author(s):  
Barbara H. Amaker ◽  
Nitya R. Ghatak ◽  
Sean A. Jebraili ◽  
Andrea Ferreira-Gonzalez ◽  
Michael J. Kornstein
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Molecular Techniques ◽  
First Case ◽  
Dural Lymphoma ◽  
Immunohistochemical Techniques

Abstract Primary dural lymphoma is rare, and few of the small number of cases reported to date have been classified using immunohistochemical techniques. To our knowledge, we report the first case of T-cell–rich B-cell lymphoma (diffuse mixed small cell and large cell) presenting as a solitary intracranial dural mass. Cytologic and frozen sections prepared during intraoperative consultation revealed a polymorphic population of lymphocytes suspicious for an inflammatory process. Permanent sections of the dura showed a diffusely infiltrating mass composed of mature lymphocytes peppered with large atypical lymphocytes. Immunohistochemical stains identified the small lymphocytes as T cells (CD3 and CD43) and the large atypical lymphocytes as B cells (CD20). Evidence of rearranged immunoglobulin heavy-chain genes demonstrated B-cell monoclonality. Differentiating between inflammatory and neoplastic lymphocytic masses of the dura obviously has important therapeutic and prognostic significance and may require immunohistochemical and molecular techniques.

Pathologic Co-Expression and Physical Interaction of c-MYC and BCL6 in B-Cell Lymphomas.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2-2 ◽  
Author(s):  
Masumichi Saito ◽  
Ryan T. Phan ◽  
Herbert C. Morse ◽  
Laura Pasqualucci ◽  
Riccardo Dalla-Favera
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Transgenic Animals ◽  
Primary Lymphoma ◽  
Physical Interaction

Abstract Deregulated expression of the proto-oncogenes BCL6 and c-MYC caused by chromosomal translocation or somatic hypermutation is common in non-Hodgkin B cell lymphoma derived from germinal center (GC) B cells, including diffuse large cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Normal GC B cells express BCL6, whereas, surprisingly, they do not express c-MYC, suggesting that the expression of this oncogene in BL and DLBCL (20% of cases) is ectopic (Klein, U. et al. Proc Natl Acad Sci U S A100, 2639–2644, 2003). Here we report that c-MYC is absent in proliferating GC B cells because it is transcriptionally suppressed by BCL6, as demonstrated by the presence of specific BCL6 binding sites in the c-MYC promoter region and by chromatin immunoprecipitation experiments showing that BCL6 is bound to these sites in vivo. Thus, c-MYC escapes BCL6-mediated suppression in lymphoma leading to the co-expression of the two transcription factors, an event never observed in immunohistochemical and gene expression profile analysis of normal GC B cells. Surprisingly, co-immunoprecipitation experiments and in vitro binding experiments indicate that, when co-expressed, BCL6 and c-MYC are physically bound in a novel complex detectable in DLBCL and BL cell lines as well as in primary lymphoma cases. The formation of the BCL6/c-MYC complex has several significant functional consequences on the function of both c-MYC and BCL6: 1) a two fold, BCL6-binding dependent increase in c-MYC half-life, an event that has been shown to contribute to its oncogenic activation; 2) a synergistic increase in the ability of both BCL6 and c-MYC to suppress MIZ1-activated transcription of the p21CIP cell cycle arrest gene; 3) MYC-dependent inhibition of BCL6 acetylation by p300, an event that physiologically inactivates BCL6 via c-MYC-mediated recruitment of HDAC. Notably, the pathologic co-expression of c-MYC and BCL6 was shown to have pathologic consequences in vivo, since double transgenic BCL6/c-MYC mice display accelerated lymphoma development and the appearance of a novel GC-derived tumor phenotype not recognizable in single transgenic animals and containing the pathologic c-MYC/BCL6 complex. Thus, the pathologic co-expression and illegitimate physical interaction of BCL6 and c-MYC leads to an increase in the constitutive activity of both oncogenes. These results identify a novel mechanism of oncogenic function for BCL6 and c-MYC and a novel tumor-specific protein complex of potential therapeutic interest.

Potent B-Cell Depletion by IMGN529, a CD37-Targeting Antibody-Maytansinoid Conjugate for the Treatment of B-Cell Malignancies,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3726-3726
Author(s):  
Jutta Deckert ◽  
Sharon Chicklas ◽  
Yong Yi ◽  
Min Li ◽  
Jan Pinkas ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Whole Blood ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
B Cell Malignancies

Abstract Abstract 3726 CD37 is a B-cell surface antigen which is widely expressed on malignant B cells in non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In normal tissues CD37 expression is limited to blood cells and lymphoid tissues. This restricted expression profile makes CD37 an attractive therapeutic target for antibodies and antibody-drug conjugates. We developed a novel anti-CD37 antibody, K7153A, which provides a unique combination of functional properties: it demonstrated strong pro-apoptotic and direct cell killing activity against NHL cell lines and could mediate effector activity such as CDC and ADCC. The antibody-maytansinoid conjugate, IMGN529, was produced by conjugation of K7153A with the potent maytansinoid, DM1, via the non-cleavable linker, SMCC. The direct cytotoxic potency of the K7153A antibody was superior to that of the CD20-directed rituximab and was further enhanced with maytansinoid conjugation in IMGN529. In vivo, IMGN529 demonstrated better anti-tumor activity than the K7153A antibody in established subcutaneous follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and CLL xenograft models in SCID mice. A single administration of IMGN529 showed similar or improved efficacy compared to anti-CD20 antibodies or standard chemotherapy where tested. Immunohistochemical (IHC) staining of formalin fixed paraffin-embedded (FFPE) NHL tissue sections was performed to evaluate CD37 expression. CD37 exhibited a similar prevalence to CD20 in subtypes of NHL such as FL, DLBCL, Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL). B-cell depletion is an important measure of efficacy for targeted therapies, such as CD20-directed antibodies, in B-cell malignancies. CD37 expression in blood cells from healthy human donors was measured by quantitative flow cytometry in comparison to CD20. The greatest CD37 expression was found in B cells at approximately 77,000 antibodies bound per cell (ABC), which was similar to CD20 expression in B cells at 95,000 ABC. In other blood cell types CD37 staining was seen at low levels, about 2,000 – 5,000 ABC, in monocytes, NK cells and T cells. In vitro depletion experiments were performed with purified peripheral blood mononuclear cells (PBMCs) and with whole blood, both derived from several healthy donors. Cells were incubated for 1 hr with 10 μg/mL of either K7153A, IMGN529, CD37-targeting TRU-016, rituximab or the anti-CD52 antibody alemtuzumab, with cell depletion determined relative to counting beads by flow cytometry. The K7153A antibody and the IMGN529 conjugate efficiently and specifically depleted B-cells in a dose-dependent manner in the context of purified PBMCs and whole blood. With purified PBMCs, both K7153A and IMGN529 caused 50–60% depletion of B cells, with little to no depletion of T cells or monocytes. IMGN529 was more potent than rituximab, which led to 30–40% B-cell depletion, or TRU-016, which caused 20–30% B-cell depletion. IMGN529 also was more specific than alemtuzumab, which depleted T-cells and monocytes as well as B cells. With whole blood samples, both K7153A and IMGN529 resulted in 30–40% B-cell depletion with no effect on T cells, NK cells or monocytes. IMGN529 was again more potent than rituximab or TRU-016, which caused approximately 10% B-cell depletion, and was more specific than alemtuzumab, which depleted the majority of T cells in addition to 40% of B cells. IMGN529 embodies a unique B-cell targeted agent as it combines the intrinsic pro-apoptotic, CDC and ADCC activities of its anti-CD37 antibody component with the potent cytotoxic mechanism provided by the targeted delivery of its maytansinoid payload. It is highly active in vitro and in vivo against B-cell lymphoma and CLL cell lines. In addition, it mediates specific B-cell depletion in vitro that is greater than B-cell depletion by CD20-directed rituximab. Together, these findings indicate that IMGN529 is a promising therapeutic candidate for the treatment of B-cell malignancies. Disclosures: Deckert: ImmunoGen, Inc.: Employment. Chicklas:ImmunoGen, Inc.: Employment. Yi:ImmunoGen, Inc.: Employment. Li:ImmunoGen, Inc.: Employment. Pinkas:ImmunoGen, Inc.: Employment. Chittenden:ImmunoGen, Inc.: Employment. Lutz:ImmunoGen, Inc.: Employment. Park:ImmunoGen, Inc.: Employment.

Increased T-Cell Activation and Th1 Cytokine Concentrations Prior to the Diagnosis of B-Cell Lymphoma in HIV Infected Patients

2012 ◽  
Vol 33 (1) ◽  
pp. 22-29 ◽  
Author(s):  
David Eric Ouedraogo ◽  
Alain Makinson ◽  
Nils Kuster ◽  
Nicolas Nagot ◽  
Pierre-Alain Rubbo ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Th1 Cytokine

scholarly journals Reproducing Transformation of Indolent B-cell Lymphoma by T-cell Immunosuppression of L.CD40 Mice

2018 ◽  
Author(s):  
Christelle Vincent-Fabert ◽  
Alexis Saintamand ◽  
Amandine David ◽  
Mehdi Alizadeh ◽  
François Boyer ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immune Suppression ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma

AbstractTransformation of an indolent B-cell lymphoma is associated with a more aggressive clinical course and poor survival. The role of immune surveillance in the transformation of a B-cell indolent lymphoma towards a more aggressive form is poorly documented. To experimentally address this question, we used the L.CD40 mouse model, which is characterized by B-cell specific continuous CD40 signaling, responsible for spleen indolent clonal or oligoclonal B-cell lymphoma after one year in 60% cases. Immunosuppression was obtained either by T/NK cell depletion or by treatment with the T-cell immunosuppressive drug cyclosporin A. Immunosuppressed L.CD40 mice had larger splenomegaly with increased numbers of B-cells in both spleen and peripheral blood. High-throughput sequencing of immunoglobulin variable segments revealed that clonal expansion was increased in immunosuppressed L.CD40 mice. Tumor B cells of immunosuppressed mice were larger with an immunoblastic aspect, both on blood smears and spleen tissue sections, with increased proliferation rate and increased numbers of activated B-cells. Collectively, these features suggest that immune suppression induced a shift from indolent lymphomas into aggressive ones. Thus, as a preclinical model, immunosuppressed L.CD40 mice reproduce aggressive transformation of an indolent B-cell tumor and highlight the role of the immune surveillance in its clinical course, opening new perspective for immune restoration therapies.Summary statementHighlighting the role of immune surveillance, transformation of indolent B-cell lymphoma into an aggressive malignancy is experimentally reproduced after T-cell immune suppression in the L.CD40 preclinical mouse model.

Assessing CD137 (4-1BB) As a Therapeutic Target in B-Cell Neoplasms,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3735-3735
Author(s):  
Adam D Cohen ◽  
Indira D Joshi ◽  
Valentin Robu ◽  
Hossein Borghaei ◽  
Tahseen I. Al-Saleem ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Tumor Cell ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Cell Proliferation

Abstract Abstract 3735 Agonist monoclonal antibodies (mAbs) to CD137, a co-stimulatory TNF receptor family member expressed on activated T and NK cells, can induce immune-mediated rejection of multiple murine tumor types, and a fully human anti-CD137 mAb, BMS-663513, is in early-phase clinical trials in solid tumors. Significant activity has been seen in murine lymphoma models, both alone and in combination with anti-CD20 mAbs, providing rationale for clinical studies in lymphoma patients. Recently, however, CD137 up-regulation on activated human B cells has been reported, with CD137 ligation causing enhanced B cell proliferation and survival. This raises the concern that mAb binding to CD137, if present, on B cell neoplasms may promote tumor cell proliferation and/or resistance to apoptosis that may counteract the beneficial effects on T and NK cells. We therefore sought to assess the expression of CD137 on a series of human cell lines and primary tumor samples from patients with B-cell neoplasms, and if expressed, to explore the consequences of ligation with the anti-CD137 agonist BMS-66513. First, archived paraffin-embedded lymph node specimens from patients with low-grade B-cell lymphoma (n=11: 5 follicular, 4 marginal zone, 2 small lymphocytic) and diffuse large B-cell lymphoma (n=15) were stained for CD137 by immunohistochemistry. Reactive tonsillar tissue served as a positive control. No CD137 expression was observed within any tumor cells. Next, fresh samples from 14 additional patients with known tumor involvement of peripheral blood or bone marrow (8 chronic lymphocytic leukemia, 1 mantle cell lymphoma, 3 myeloma, 2 marginal zone lymphoma) were analyzed by multi-color flow cytometry. Again, no CD137 expression was observed on the gated neoplastic cells. Baseline surface expression of CD137 was similarly absent in all B cell-derived lines tested (Raji, FCTxFL2, FSCCL, DoHH2, Jeko-1, RPMI8226). However, activation with PMA/Ionomycin could reproducibly induce CD137 expression (% positive: 0.17% → 91%) after 24 hours in 1 of the lines: the follicular lymphoma FSCCL. Interestingly, this was the only line tested that lacked constitutive expression of CD137 ligand (CD137L), suggesting some reciprocal regulation of ligand and receptor expression. Despite this up-regulation of CD137, in vitro ligation of PMA/Ionomycin-activated FSCCL cells with BMS-66513 did not further increase tumor cell proliferation, nor protect the cells from activation-induced cell death, in contrast to effects of CD137 ligation reported in normal B cells (Zhang et al, J Immunol 2010; 184:787). Similarly, BMS-663513 treatment of activated, CD137+ FSCCL cells did not diminish the apoptosis induced by doxorubicin or bortezomib treatment. In addition, FSCCL cells recovered from ascites 7 and 14 days following intraperitoneal injection in SCID mice did not express CD137, implying that CD137 up-regulation is not occurring in vivo during tumor growth. Finally, treatment of FSCCL cells with rituximab, either in vitro or in vivo, did not induce CD137 expression. In conclusion, we demonstrate a lack of steady-state CD137 expression on malignant B cells, confirming the prior study by Houot et al (Blood 2009; 114:3431) and extending these findings to include CLL/SLL for the first time. While CD137 could be induced in a single cell line upon non-specific activation, CD137 expression on FSCCL cells was not seen under physiologic conditions likely to be encountered in the clinical setting, consistent with the primary patient data. Furthermore, even when CD137 was expressed, ligation with the agonist anti-CD137 mAb BMS-663513 did not provide a pro-proliferative or anti-apoptotic signal. These studies provide reassurance and further rationale for exploring agonist anti-CD137 antibodies as therapies for B cell neoplasms. Disclosures: Borghaei: Lilly, Genentech, Amgen, Pfizer: Honoraria, Research Funding. Jure-Kunkel:Bristol Meyers Squibb: Employment.

The Diffuse Large B-Cell Lymphoma Infiltrating Macrophage Transcriptome Signature Is Enriched for Both M1 and M2 Genes and Provides an Excellent Platform for Functional Validation of Macrophage Biology in DLBCL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 790-790
Author(s):  
Rita Coutinho ◽  
Aaron M. Newman ◽  
Guglielmo Rossignoli ◽  
William Day ◽  
Faridah Miraki-Moud ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Bioinformatics Analysis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Functional Validation ◽  
Fc Fragment ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 790 Several investigators have defined gene expression profiling (GEP) signatures in Diffuse Large B-cell Lymphoma (DLBCL) enriched for macrophage and stromal genes, suggesting an active innate immune response against lymphoma. We hypothesize that the malignant B-cells drive tumor-associated macrophage (TAM) dysfunction in a subset of patients with DLBCL which is relevant for their biology and prognosis. We performed GEP on TAM from diagnostic DLBCL in order to recognise key genes and pathways open to functional validation. Single cell suspensions from 8 DLBCL and 8 reactive lymph nodes were used in this study. TAMs were flow sorted using CD36 expression. cDNA synthesis and amplification was performed using the Nugen Ovation Pico WTA system and the Affymetrix GeneChip human gene 1.0 ST platform was used. We used bioinformatics analysis of GEP data from DLBCL whole tumors, DLBCL purified B-cells, in vitro manipulated macrophages and other immune cells in order to define macrophage-enriched genes as well as specific M1/M2 signatures. We identified a 221 gene signature that significantly distinguished DLBCL TAMs from control macrophages, with 165 genes upregulated and 56 genes downregulated. Moreover, a comparative transcriptome analysis of 22 diverse immune cell phenotypes/activation states (IRIS: GSE22886) revealed that 26% of these genes are highly macrophage-enriched. Gene Ontology analysis revealed an over-representation for transcripts involved in inflammatory response (p 6.8×10−23), wound healing (p 1.9×10−20), chemotaxis (p 3.2 ×10−9), and cell motility (p 1.7×10−7). Upregulated genes in TAMs included well known M1 (complement components, CXCL9 or CXCL10) as well as M2 genes (MSR, CD163 or MARCO) (Table 1). In our signature, there was enrichment for M1 compared to M2 genes as defined by bioinformatics analysis. TAMs showed overexpression of the CSF1R gene as well as the chemokines CCL2 and CCL5, suggesting an autocrine feed-back loop of macrophage chemotaxis and survival in DLBCL. Moreover, TAMs showed upregulation of the lymphocyte attractants CCL20, CXCL9 and CXCL10, together with T-cell immunosupressants indoleamine 2,3-dioxygenase 1 and PD-L1, which would support a role for macrophages in T-cell recruitment and dysfunction in DLBCL. We also saw strong upregulation of 7 metallothionein isoforms in TAMs. These are proteins known to be expressed in macrophages and linked to response to oxidative damage, modulation of inflammation and cell proliferation. However their role in cancer microenvironment is unclear. We describe for the first time the GEP from DLBCL TAMs. The TAM transcriptome has partial overlapping genes with both M1 and M2 gene signatures, but also has a characteristic GEP potentially driven by their presence in the DLBCL microenvironment. Although further molecular and functional validation is required, this data provides a platform of genes which serve as excellent candidates for future exploration to understand DLBCL pathogenesis and to define new therapeutic targets. Table 1: Genes of particular interest represented in our TAM signature. Probe collapse was done using the highest expression. The Benjamini-Hochberg multiple hypothesis test was used to determine significance (FDR 0.05). Gene IDs Gene description Log2 Fold Change Adjusted p value MT1E-H, L, M, X, MT2A metallothionein 1E-H, 1M, 1X, 2A 2.3 – 4.4 0.00145 - 0.00017 C1QA, B and C complement component 1, q subcomponent, A, B and C chains 3.1 – 3.6 0.00136 - 0.00255 C2 complement component 2 3.2 0.00136 CCL2, 4, 5, 8, 20 chemokine (C-C motif) ligand 2, 4, 5, 8 and 20 2.4 - 3.7 0.046 - 0.00130 CD163 CD163 molecule 4.6 0.00025 CD14 CD14 molecule 3.4 0.00091 CD274 CD274 molecule 3.7 0.00447 CSF1R colony stimulating factor 1 receptor 2.1 0.00886 CXCL9-11 chemokine (C-X-C motif) ligand 9, 10 and 11 4.2 – 4.4 0.012 - 0.00158 FCGR1B Fc fragment of IgG, high affinity Ib, receptor (CD64) 4.9 0.00091 FCGR2A Fc fragment of IgG, low affinity IIa, receptor (CD32) 3.3 0.00139 FCGR3A Fc fragment of IgG, low affinity IIIa, receptor (CD16a) 5.2 0.00011 IDO1 indoleamine 2,3-dioxygenase 1 4.8 0.00232 MARCO macrophage receptor with collagenous structure 2.6 0.02029 MSR1 macrophage scavenger receptor 1 3.7 0.01467 Disclosures: Gribben: Celgene: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

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