ORCID Profile
0000-0003-1000-5393
Current Organisations
University of Cambridge
,
University of Aberdeen
,
Royal Australasian College of Physicians
,
University of Queensland
,
Royal College of Physicians
,
Princess Alexandra Hospital
,
The Royal College of Pathologists
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Publisher: Informa UK Limited
Date: 06-2010
Publisher: American Association for Cancer Research (AACR)
Date: 04-2017
DOI: 10.1158/1078-0432.CCR-16-1576
Abstract: Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival. Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline “R-CHOP” therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS). Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P & 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%–79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%–88.5% P = 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%–76.6%) versus 72.6% (95% CI, 58.8%–82.4%, P = 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell ersity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy. Clin Cancer Res 23(7) 1820–8. ©2016 AACR.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.BLRE.2022.100969
Abstract: Broad activation of host T-cell immunity by immune checkpoint blockade, has revolutionized the treatment of some but not all B-cell lymphoproliferative disorders (LPDs). The challenge for next generation immunotherapeutics, is to successfully induce anti-tumor specific T-cell immunity across a range of B-LPDs, without provoking immune-related adverse events. An emerging strategy is to target neoantigens. Neoantigens are immunogenic peptides, unique to malignant cells, that are presented to T-cells via human leukocyte antigens. Neoantigens most commonly arise from non-synonymous mutations but can also be derived from tumor specific alterations along the protein biosynthesis pathway. B-cell LPDs uniquely express a clonal B-cell receptor (BCR) idiotype, consisting of immunoglobulin genes that undergo recombination and somatic hypermutation. Notably, the BCR idiotype can also give rise to 'immunoglobulin neoantigens'. Here, we provide an overview of current strategies to identify and validate immunoglobulin and non-immunoglobulin neoantigens as well as summarizing studies investigating neoantigens within B-cell LPDs.
Publisher: American Society of Hematology
Date: 08-07-2019
DOI: 10.1182/BLOODADVANCES.2019000251
Abstract: In advanced-stage diffuse large B-cell lymphoma (DLBCL), the presence of an activated B-cell phenotype or a non–germinal center (GCB) phenotype, coexpression of MYC and BCL2 by immunohistochemistry, and the cooccurrence of MYC and BCL2 or BCL6 rearrangements are associated with inferior outcomes. It is unclear whether these variables remain prognostic in stage I/II patients. In this retrospective study, we evaluated the prognostic impact of cell of origin (COO), as well as dual-expressor (DE) status and molecular double-hit (DH) status, in stage I/II DLBCL by positron emission tomography with computed tomography (PET-CT). A total of 211 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimens, with or without radiotherapy, was included. The median follow-up in the entire cohort was 4 years (range, 0.4-9.4), with estimated 4-year progression-free survival (PFS) and overall survival (OS) rates of 85% (95% confidence interval [CI], 79-89) and 88% (95% CI, 83-92), respectively. By univariable analysis, DE (PFS: hazard ratio [HR], 1.27 95% CI, 0.58-2.81, P = .55 and OS: HR, 1.40 95% CI, 0.60-3.30 P = .44), DH (PFS: HR, 1.21 95% CI, 0.27-5.31 P = .80 and OS: HR, 0.61 95% CI, 0.08-4.73 P = .64), and non-GCB status (PFS: HR, 1.59 95% CI, 0.83-3.03 P = .16 and OS: HR, 1.80 95% CI, 0.89-3.67 P = .10) were associated with poorer outcomes. In patients with PET-CT–defined stage I/II DLBCL treated with R-CHOP–like therapy, with or without radiation, COO and DE and DH status were not significantly associated with inferior PFS or OS.
Publisher: American Society of Hematology
Date: 24-12-2020
Abstract: Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.
Publisher: Springer Science and Business Media LLC
Date: 21-07-2011
DOI: 10.1038/GENE.2011.50
Abstract: Many primary immunodeficiency disorders of differing etiologies have been well characterized, and much understanding of immunological processes has been gained by investigating the mechanisms of disease. Here, we have used a whole-genome approach, employing single-nucleotide polymorphism and gene expression microarrays, to provide insight into the molecular etiology of a novel immunodeficiency disorder. Using DNA copy number profiling, we define a hyperploid region on 14q11.2 in the immunodeficiency case associated with the interleukin (IL)-25 locus. This alteration was associated with significantly heightened expression of IL25 following T-cell activation. An associated dominant type 2 helper T cell bias in the immunodeficiency case provides a mechanistic explanation for recurrence of infections by pathogens met by Th1-driven responses. Furthermore, this highlights the capacity of IL25 to alter normal human immune responses.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 05-05-2023
DOI: 10.1111/IMJ.16078
Abstract: Diffuse large B‐cell lymphoma (DLBCL) is the most frequent aggressive lymphoma seen in clinical practice. Despite huge strides in understanding its biology, front‐line therapy has remained unchanged for decades. Roughly one‐third of patients have primary refractory or relapse following the end of conventional first‐line therapy. The outcome of patients with primary refractory disease and those with early relapse (defined as relapse less than 1 year from the end of therapy) is markedly inferior to those with later relapse and is exemplified by dismal overall survival. In this article, the authors term patients with features that identify them as being at particularly high‐risk for either primary refractory disease or early relapse, as ‘ultra‐high‐risk’. As new treatment options become established (e.g. bispecific T‐cell engagers, chimeric antigen receptor ‘CAR’ T‐cells and antibody–drug conjugates), it is likely that there will be a push to incorporate some of these agents into the first‐line setting for patients identified as ultra‐high‐risk. In this review, the authors outline advances in positron emission tomography, widely available laboratory assays and clinical prognosticators, which can detect a high proportion of patients with ultra‐high‐risk disease. Since these approaches are pragmatic and able to be adopted widely, they could be incorporated into routine clinical practice.
Publisher: Informa UK Limited
Date: 2006
Publisher: Informa UK Limited
Date: 12-2011
Publisher: Wiley
Date: 18-03-2004
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1080/003130200500368303
Abstract: The aetiology of lymphomas is poorly understood and the striking increase in its incidence rate in developed societies remains unexplained. The concept of lymphoma as a virally-induced malignancy is not surprising since viruses are implicated in approximately 15% of all cancers. However, lymphoma represents a complex multistep process and, although viral associations have been identified, integration of the available epidemiological and scientific data poses substantial questions. The study of oncogenic viruses has and will continue to yield major insights into the pathogenesis of lymphoma. Further research is likely to uncover new lymphoma associations between both known and as yet unidentified viruses, may provide cellular and pharmacological targeted antiviral therapy strategies for the treatment of malignant lymphoma, and ultimately may generate the most promising avenue for lymphoma prevention.
Publisher: American Society of Hematology
Date: 10-2006
DOI: 10.1182/BLOOD-2006-04-015164
Abstract: In Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg (HRS) cells constitute only 0.5% of 10% of the diseased tissue. The surrounding cellular infiltrate is enriched with T cells that are hypothesized to modulate antitumor immunity. We show that a marker of regulatory T cells, LAG-3, is strongly expressed on infiltrating lymphocytes present in proximity to HRS cells. Circulating regulatory T cells (CD4+ CD25hi CD45 ROhi, CD4+ CTLA4hi, and CD4+ LAG-3hi) were elevated in HL patients with active disease when compared with remission. Longitudinal profiling of EBV-specific CD8+ T-cell responses in 94 HL patients revealed a selective loss of interferon-γ expression by CD8+ T cells specific for latent membrane proteins 1 and 2 (LMP1/2), irrespective of EBV tissue status. Intratumoral LAG-3 expression was associated with EBV tissue positivity, whereas FOXP3 was linked with neither LAG-3 nor EBV tissue status. The level of LAG-3 and FOXP3 expression on the tumor-infiltrating lymphocytes was coincident with impairment of LMP1/2-specific T-cell function. In vitro pre-exposure of peripheral blood mononuclear cells to HRS cell line supernatant significantly increased the expansion of regulatory T cells and suppressed LMP-specific T-cell responses. Deletion of CD4+ LAG-3+ T cells enhanced LMP-specific reactivity. These findings indicate a pivotal role for regulatory T cells and LAG-3 in the suppression of EBV-specific cell-mediated immunity in HL.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JIM.2018.12.002
Abstract: Current HLA-typing methods are typically designed to provide exquisitely-detailed identification of multiple HLA-alleles to satisfy the requirements for organ and bone marrow transplantation or genetic studies. Many human immunological studies, on the other hand, focus around only a small number of HLA alleles that are abundant or of relevance to specific diseases. Consequently, for such studies, many HLA typing approaches are not cost-effective and are potentially complicated, slow and not easily performed in-house. Work-flow would be streamlined by a simple, inexpensive and rapid typing method able to be performed in-house. We outline a straightforward approach that provides appropriate data for much immunological research. In a predominantly Caucasian population, flow cytometry using anti-HLA-A2, -B8 and -B7 antibodies consistently and accurately screened for s les carrying the highly-abundant HLA class I alleles HLA-A*02:01, -B*08:01 and -B*07:02 that form the focus of immunological studies. Next, we describe a straightforward and simple strategy for design and use of allele-specific PCR primers to identify, at high-resolution, alleles of interest. When combined with a simple gDNA extraction technique this provides reliable, simple and inexpensive in-house HLA typing demonstrated here for highly-abundant HLA class I alleles.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 23-08-2021
DOI: 10.1111/BJH.17789
Abstract: Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL n = 58), transformed indolent lymphomas (follicular [tFL], n = 16 marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.
Publisher: No publisher found
Date: 2014
DOI: 10.1111/BCP.12318
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Society of Hematology
Date: 19-12-2019
Abstract: This article reports a novel mechanism by which Epstein-Barr virus (EBV) microRNA (miRNA) plays a role to fine-tune the expression of LMP1-driven lification of inhibitory checkpoint programmed death ligand 1 (PD-L1) and PD-L2 in EBV+ diffuse large B-cell lymphoma. Identification and understanding of the immune checkpoint regulation via miRNA may enable potential novel RNA-based therapies to emerge.
Publisher: Springer Science and Business Media LLC
Date: 10-2001
Abstract: As a consequence of the significantly larger inoculum of lymphoid cells present in peripheral blood stem cell (PBSC) harvests compared to bone marrow (BM), it is possible that autoPBSCT recipients may have an earlier and*or enhanced response to vaccines. Until data to confirm this become available, the European Blood and Marrow Transplantation Association (EBMT) recommend that all transplant recipients be immunized in the same way regardless of stem cell source. We performed a prospective study comparing serological responses to influenza, pneumococcal polysaccharide and tetanus toxoid vaccines between autoPBSCT with autoBMT recipients. Antibody responses in sibling HLA-matched allogeneic BMT (alloBMT) survivors were also evaluated. All vaccines were administered within the first 2 years after stem cell transplantation. Fifty patients were enrolled. The time of vaccination after transplant was similar between autoPBSCT (mean 11 months for each vaccine) and autoBMT recipients (mean 12 months except 13 months for tetanus toxoid) (P = NS). Serological responses were poor and no significant difference in response to any of the vaccines used was seen between the three transplant cohorts. We provide no evidence that current EBMT guidelines be modified. Large prospective vaccine studies are needed to address the issue more fully.
Publisher: Wiley
Date: 12-02-2014
DOI: 10.1111/TAN.12295
Abstract: Immune thrombocytopenia (ITP) is an autoimmune disorder of unknown aetiology, characterised by an isolated low platelet count in the absence of other identifiable causes. Genes influencing activation of the immune system have been identified as influencing predisposition. Killer cell immunoglobulin-like receptors (KIR) control T-cell and natural killer (NK) cell function via inhibitory and activating signalling pathways. The inhibitory KIR2DL3, KIR3DL2 and KIR3DL1 are up-regulated in the T-cells of patients with ITP in remission relative to those with active disease, and an association of KIR2DS2 and KIR2DL2 with ITP has also been reported. No comprehensive KIR analysis in ITP has been reported. We performed genotyping of all currently known KIR genes using sequence specific primer polymerase chain reaction (SSP-PCR) on a cohort of 83 adult patients with ITP (chronic ersistent or relapsed primary ITP identified by defined criteria) and 106 age matched healthy white volunteers. Non-white patients were not included in the analysis. There was an over-representation of KIR2DS3 (known to be in linkage disequilibrium with KIR2DS2 and 2DL2) and under-representation of KIR2DS5 (also protective against other immune mediated disorders) in adult ITP [odds ratio (OR) = 0.16, confidence interval (CI) 0.08-0.32, P < 0.001]. By multivariable binary logistic regression to adjust for age, sex and the effects of other KIR genes, the presence of KIR2DS2/2DL2 with KIR2DS5 abrogated the risk of KIR2DS2/2DL2 and the protective benefit of KIR2DS5. Further studies are required to establish the mechanistic basis for these observations and their potential impact on ITP therapy.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1080/14653240701320288
Abstract: The use of cellular therapy in Australia has been limited by the number of facilities deemed acceptable for the preparation of T cells for immunotherapy. In spite of this, a number of trials using cellular immunotherapy have been conducted and a number are underway or are in the planning stage, and selected ex les of these are summarized in this review.
Publisher: Impact Journals, LLC
Date: 30-08-2013
Publisher: American Association for Cancer Research (AACR)
Date: 03-11-2022
DOI: 10.1158/2326-6066.CIR-22-0793
Abstract: Chimeric antigen receptor (CAR) T-cell therapy has yielded remarkable and durable responses for some patients with relapsed and refractory blood cancers. However, life-threatening toxicities such as immune effector cell–associated neurotoxicity syndrome (ICANS) remain a challenge for broad delivery of such therapies. In this issue, Tang and colleagues demonstrate an association between hypophosphatemia and CAR T cell–induced ICANS. Prospective studies are required to establish if phosphate monitoring is an early predictor for ICANS occurrence and if maintenance of phosphate levels has a role as a preventative strategy. See related article by Tang et al., p. 1433 (4).
Publisher: Springer Science and Business Media LLC
Date: 21-05-2014
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.TRIM.2015.02.005
Abstract: Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous in iduals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation.
Publisher: American Association for Cancer Research (AACR)
Date: 2014
DOI: 10.1158/1078-0432.CCR-13-1024
Abstract: Purpose: Although microRNAs (miRNA) show potential as diagnostic biomarkers in cancer, their role as circulating cell-free disease response biomarkers remains unknown. Candidate circulating miRNA biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin–Reed–Sternberg (HRS) cells and/or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, embedded within a benign microenvironment, the composition of which is distinct from that seen in healthy lymph nodes. Experimental Design: Microarray profiling of more than 1,000 human miRNAs in 14 cHL primary tissues and eight healthy lymph nodes revealed a number of new disease node–associated miRNAs, including miR-494 and miR-1973. Using quantitative real-time PCR (qRT-PCR), we tested the utility of these, as well as previously identified disease node–associated plasma miRNAs (including miR-21 and miR-155), as disease response biomarkers in a prospective cohort of 42 patients with cHL. Blood s les were taken in conjunction with radiologic imaging at fixed time points before, during, and after therapy. Absolute quantification was used so as to facilitate implementation in diagnostic laboratories. Results: Levels of miR-494, miR-1973, and miR-21 were higher in patients than control (n = 20) plasma (P = 0.004, P = 0.007, and P & 0.0001, respectively). MiR-494 and miR-21 associated with Hasenclever scores ≥3. Strikingly, all three miRNAs returned to normal at remission (P = 0.0006, P = 0.0002, and P & 0.0001 respectively). However, only miR-494 and miR-1973 reflected interim therapy response with reduction being more pronounced in patients achieving complete versus partial responses (P = 0.043 and P = 0.0012, respectively). Conclusion: Our results demonstrate that in patients with cHL, circulating cell-free miRNAs can reflect disease response once therapy has commenced. Clin Cancer Res 20(1) 253–64. ©2013 AACR.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1111/AJT.12211
Abstract: We performed a multicenter, International analysis of solid organ transplant (SOT)-related primary central nervous system (PCNS) posttransplant lymphoproliferative disease (PTLD). Among 84 PCNS PTLD patients, median time of SOT-to-PTLD was 54 months, 79% had kidney SOT, histology was monomorphic in 83% and tumor was EBV+ in 94%. Further, 33% had deep brain involvement, 10% had CSF involvement, while none had ocular disease. Immunosuppression was reduced in 93% additional first-line therapy included high-dose methotrexate (48%), high-dose cytarabine (33%), brain radiation (24%) and/or rituximab (44%). The overall response rate was 60%, while treatment-related mortality was 13%. With 42-month median follow-up, three-year progression-free survival (PFS) and overall survival (OS) were 32% and 43%, respectively. There was a trend on univariable analysis for improved PFS for patients who received rituximab and/or high-dose cytarabine. On multivariable Cox regression, poor performance status predicted inferior PFS (HR 2.61, 95% CI 1.32-5.17, p = 0.006), while increased LDH portended inferior OS (HR 4.16, 95% CI 1.29-13.46, p = 0.02). Moreover, lack of response to first-line therapy was the most dominant prognostic factor on multivariable analysis (HR 8.70, 95% CI 2.56-29.57, p = 0.0005). Altogether, PCNS PTLD appears to represent a distinct clinicopathologic entity within the PTLD spectrum that is associated with renal SOT, occurs late, is monomorphic and retains EBV positivity.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 11-01-2007
DOI: 10.1111/J.1365-2141.2006.06482.X
Abstract: Immunosuppression following solid organ transplantation results in impaired T-cell immunity and risk of Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disorders (PTLD). The B-cell targeting antibody rituximab has efficacy in PTLD. As B cells are the principle reservoir for EBV, we investigated the effect of rituximab on the persistence of EBV-specific CD8(+) T-cell immunity. To avoid the confounding factor of concurrent immunosuppression to prevent transplant rejection, immunity was analysed in non-transplanted lymphoma patients (i.e. a non-PTLD setting). Cytomegalovirus-specific T-cell immunity was assessed as an internal control. Our data demonstrated that circulating B cells were not critical for maintaining EBV-specific T-cell immunity.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 22-04-2008
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1111/AJT.12858
Abstract: Primary central nervous system (pCNS) posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation characterized by poor outcome. In contrast to systemic PTLD, Epstein-Barr virus (EBV)-association of pCNS PTLD is almost universal, yet viral and cellular data are limited. To identify differences in the pattern of EBV-association of pCNS and systemic PTLD, we analyzed the expression of latent and lytic EBV transcripts and the viral and cellular microRNAome in nine pCNS (eight EBV-associated) and in 16 systemic PTLD s les (eight EBV-associated). Notably although 15/16 EBV-associated s les exhibited a viral type III latency pattern, lytic transcripts were also strongly expressed. Members of the ebv-miR-BHRF1 and ebv-miR-BART clusters were expressed in virtually all EBV-associated PTLD s les. There were 28 cellular microRNAs differentially expressed between systemic and pCNS PTLD. pCNS PTLD expressed lower hsa-miR-199a-5p/3p and hsa-miR-143/145 (implicated in nuclear factor kappa beta and c-myc signaling) as compared to systemic PTLD. Unsupervised nonhierarchical clustering of the viral and cellular microRNAome distinguished non-EBV-associated from EBV-associated s les and identified a separate group of EBV-associated pCNS PTLD that displayed reduced levels of B cell lymphoma associated oncomiRs such as hsa-miR-155, -21, -221 and the hsa-miR-17-92 cluster. EBV has a major impact on viral and cellular microRNA expression in EBV-associated pCNS PTLD.
Publisher: Elsevier BV
Date: 05-2020
Publisher: American Society of Hematology
Date: 27-08-2009
Publisher: Informa UK Limited
Date: 18-12-2018
Publisher: Wiley
Date: 10-02-2019
DOI: 10.1111/BJH.15778
Publisher: Informa UK Limited
Date: 02-2006
Abstract: Following Epstein and colleagues' ground-breaking discovery of Epstein-Barr virus by electron microscopy of Burkitt's lymphoma cell lines, there came the observation that Epstein-Barr virus induces immortalization of B cells in vitro. Thus, initial hopes were of a virus confined to equatorial Africa with a causal link to a particular subtype of childhood lymphoma. Over the past 40 years there has been great progress towards understanding the biology and epidemiology of Epstein-Barr virus, which conclusively show that these early ideas were overly simplistic. It is now known that Epstein-Barr virus has a seroprevalence of approximately 95% worldwide, and persists for life within host B lymphocytes. Infection in New World primates leads to lymphoma and inoculation of peripheral blood mononuclear cells from Epstein-Barr virus-seropositive subjects into severe combined immunodeficiency mice results in B-cell lymphoproliferative disorders. Epstein-Barr virus is now known to be implicated in a range of lymphoid and other malignancies, and this association will be the subject of this review.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.BLRE.2015.06.002
Abstract: Gene expression profiling has implicated several intracellular signalling cascades, including the JAK/STAT pathway, in the pathogenesis of particular subtypes of lymphoma. In marked contrast to the situation in patients with either acute lymphoblastic leukaemia or a myeloproliferative neoplasm, JAK2 coding sequence mutations are rare in lymphoma patients with an activated JAK/STAT "signature". This is instead the consequence of mutational events that result in the increased expression of non-mutated JAK2 positively or negatively affect the activity of other components of the JAK/STAT pathway or establish an autocrine signalling loop that drives JAK-mediated cytokine-independent proliferation. Here, we detail these genetic lesions, their functional consequences, and impact on patient outcome. In light of the approval of a JAK1/JAK2 inhibitor for the treatment of myelofibrosis, and preliminary studies evaluating the efficacy of other JAK inhibitors, the therapeutic potential of compounds that target JAK/STAT signalling in the treatment of patients with lymphoma is also discussed.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487442.V1
Abstract: Supplementary Data from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-02-2020
DOI: 10.1200/JCO.19.02935
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/JCO.18.02365
Abstract: Understanding the immunobiology of the 15% to 30% of patients with follicular lymphoma (FL) who experience progression of disease within 24 months (POD24) remains a priority. Solid tumors with low levels of intratumoral immune infiltration have inferior outcomes. It is unknown whether a similar relationship exists between POD24 in FL. Digital gene expression using a custom code set—five immune effector, six immune checkpoint, one macrophage molecules—was applied to a discovery cohort of patients with early- and advanced-stage FL (n = 132). T-cell receptor repertoire analysis, flow cytometry, multispectral immunofluorescence, and next-generation sequencing were performed. The immune infiltration profile was validated in two independent cohorts of patients with advanced-stage FL requiring systemic treatment (n = 138, rituximab plus cyclophosphamide, vincristine, prednisone n = 45, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), with the latter selected to permit comparison of patients experiencing a POD24 event with those having no progression at 5 years or more. Immune molecules showed distinct clustering, characterized by either high or low expression regardless of categorization as an immune effector, immune checkpoint, or macrophage molecule. Low programmed death-ligand 2 (PD-L2) was the most sensitive/specific marker to segregate patients with adverse outcomes therefore, PD-L2 expression was chosen to distinguish immune infiltration HI (ie, high PD-L2) FL biopsies from immune infiltration LO (ie, low PD-L2) tumors. Immune infiltration HI tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. Of note, the immune infiltration LO subset of patients with FL was enriched for POD24 events (odds ratio [OR], 4.32 c-statistic, 0.81 P = .001), validated in the independent cohorts (rituximab plus cyclophosphamide, vincristine, prednisone: OR, 2.95 c-statistic, 0.75 P = .011 and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: OR, 7.09 c-statistic, 0.88 P = .011). Mutations were equally proportioned across tissues, which indicated that degree of immune infiltration is capturing aspects of FL biology distinct from its mutational profile. Assessment of immune-infiltration by PD-L2 expression is a promising tool with which to help identify patients who are at risk for POD24.
Publisher: American Association for Cancer Research (AACR)
Date: 11-03-2022
DOI: 10.1158/1078-0432.CCR-21-4283
Abstract: In a post hoc analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with IDH1/2 wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype (IDH-wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of IDH1/2wt and H3F3Awt tumors with presence of TERT promoter mutations and/or EGFR lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including MGMT promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, IDH-wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). MGMT promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. In this cohort of patients with glioblastoma, IDH-wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of MGMT promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population.
Publisher: American Chemical Society (ACS)
Date: 17-05-2016
DOI: 10.1021/ACS.ANALCHEM.5B04446
Abstract: The front-line treatment for adult acute myeloid leukemia (AML) is anthracycline-based combination chemotherapy. However, treatment outcomes remain suboptimal with relapses frequently observed. Among the mechanisms of treatment failure is multidrug resistance (MDR) mediated by the ABCB1, ABCC1, and ABCG2 drug-efflux transporters. Although genetic and phenotypic heterogeneity between leukemic blast cells is a well-recognized phenomenon, there remains minimal data on differences in MDR activity at the in idual cell level. Specifically, functional assays that can distinguish the variability in MDR activity between in idual leukemic blasts are lacking. Here, we outline a new dielectrophoretic (DEP) chip-based assay. This assay permits measurement of drug accumulation in single cells, termed same-single-cell analysis in the accumulation mode (SASCA-A). Initially, the assay was optimized in pretherapy s les from 20 adults with AML whose leukemic blasts had MDR activity against the anthracyline daunorubicin (DNR) tested using multiple MDR inhibitors. Parameters tested were initial drug accumulation, time to achieve signal saturation, fold-increase of DNR accumulation with MDR inhibition, ease of cell trapping, and ease of maintaining the trapped cells stationary. This enabled categorization into leukemic blast cells with MDR activity (MDR(+)) and leukemic blast cells without MDR activity (MDR(-ve)). Leukemic blasts could also be distinguished from benign white blood cells (notably these also lacked MDR activity). MDR(-ve) blasts were observed to be enriched in s les taken from patients who went on to enter complete remission (CR), whereas MDR(+) blasts were frequently observed in patients who failed to achieve CR following front-line chemotherapy. However, pronounced variability in functional MDR activity between leukemic blasts was observed, with MDR(+) cells not infrequently seen in some patients that went on to achieve CR. Next, we tested MDR activity in two paired AML patient s les. Pretherapy s les taken from patients that achieved CR to front-line chemotherapy were compared with s les taken at time of subsequent relapse. MDR(+) cells were frequently observed in leukemic blast cells in both pretherapy and relapsed s les, consistent with MDR as a mechanism of relapse in these patients. We demonstrate the ability of a new DEP microfluidic chip-based assay to identify heterogeneity in MDR activity in leukemic blasts. The test provides a platform for future studies to characterize the mechanistic basis for heterogeneity in MDR activity at the in idual cell level.
Publisher: American Society of Hematology
Date: 22-06-2021
DOI: 10.1182/BLOODADVANCES.2020004051
Abstract: Data on the prognostic impact of pretherapy 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) in follicular lymphoma (FL) is conflicting. The predictive utility of pretherapy total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) on outcome appears to vary between regimens. Chemoimmunotherapies vary in the extent of T-cell depletion they induce. The role of intratumoral T cells on pretherapy FDG-PET parameters is undefined. We assessed pretherapy FDG-PET parameters and quantified intratumoral T cells by multiple methodologies. Low intratumoral T cells associated with approximately sixfold higher TMTV, and FL nodes from patients with high TMTV showed increased malignant B-cell infiltration and fewer clonally expanded intratumoral CD8+ and CD4+ T-follicular helper cells than those with low TMTV. However, fluorescently labeled glucose uptake was higher in CD4+ and CD8+ T cells than intratumoral B cells. In patients with FDG-PET performed prior to excisional biopsy, SUVmax within the subsequently excised node associated with T cells but not B cells. In summary, TMTV best reflects the malignant B-cell burden in FL, whereas intratumoral T cells influence SUVmax. This may contribute to the contradictory results between the prognostic role of different FDG-PET parameters, particularly between short- and long-term T-cell–depleting chemoimmunotherapeutic regimens. The impact of glucose uptake in intratumoral T cells should be considered when interpreting pretherapy FDG-PET in FL.
Publisher: American Society of Hematology
Date: 11-2003
DOI: 10.1182/BLOOD-2002-12-3689
Abstract: To investigate the mechanisms of human T-cell reconstitution following allogeneic hemopoietic stem cell transplantation (alloSCT), we analyzed the clonal composition of human cytomegalovirus (HCMV)-specific or Epstein-Barr virus (EBV)-specific CD8+ T cells in 10 alloSC transplant recipients and their donors. All virus-specific CD8+ T-cell clones isolated from recipients after alloSCT contained DNA of donor origin. In all 6 D+/R+ sibling alloSCTs from seropositive donors into seropositive recipients, donor virus-specific clones transferred in the allograft underwent early expansion and were maintained long term in the recipient. In contrast, in 2 of 3 HCMV D+/R- alloSC transplant recipients in whom there was no detectable HCMV infection, donor HCMV-specific clones were undetectable, whereas donor EBV-specific clones were maintained in the same EBV-seropositive recipients, suggesting that transferred clones require antigen for their maintenance. Following D-/R+ transplantation from 3 seronegative donors into seropositive recipients, a delayed primary virus-specific CD8+ T-cell response was observed, in which the T cells contained donor DNA, suggesting that new antigen-specific T cells arose in the recipient from donor-derived progenitors. In 2 of 4 HCMV D+/R+ sibling allograft recipients the clonal composition underwent ersification as compared with their donors, with delayed persistent expansion of HCMV-specific clones that were undetectable in the donor or in the recipient during the early months after transplantation this ersification may represent expansion of new clones generated from donor-derived progenitors. We conclude that, following alloSCT, late ersification of the HCMV-specific CD8+ T-cell clonal repertoire can occur in response to persistent viral antigen.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2012
Publisher: American Society of Hematology
Date: 19-04-2018
DOI: 10.1182/BLOOD-2017-07-796342
Abstract: Expansion of PD-1+ CD3−CD56hiCD16-ve NK cells and PD-L1+ monocytes/macrophages is more prominent in cHL than DLBCL. PD-1 blockade reverses the immune evasion mediated by the interaction of PD-1+ NK cells and PD-L1+ monocytes/macrophages.
Publisher: Future Medicine Ltd
Date: 06-2011
DOI: 10.2217/IMT.11.56
Abstract: Evaluation of: Lin Y, Gustafson MP, Bulur PA, Gastineau DA, Witzig TE, Dietz AB: Immunosuppressive CD14 + HLA-DR low/- monocytes in B-cell non-Hodgkin’s lymphoma. Blood 117, 872–881 (2011). The mechanisms of systemic immunosuppression in B-cell non-Hodgkin’s lymphoma (NHL) are poorly characterized. Lin and colleagues collected blood from 40 NHL patients prior to therapy. Monocytes from NHL patients suppressed T-cell proliferation, were unresponsive to Toll-like receptor stimulation by CpG and resistant to maturing into CD83 + dendritic cells. This suppression was mediated in part through arginine metabolism, as exogenous arginine supplementation reversed this, and NHL patients had elevated arginase I in their plasma. These cells had decreased HLA-DR and TNF-α receptor II (CD120b) expression compared with controls. Patients with increased ratios of CD14 + HLA-DR low/- monocytes had more advanced disease and suppressed immune functions, indicating that CD14 + HLA-DR low/- monocytes are a pivotal and profoundly effective contributor to systemic immunosuppression in NHL.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 14-07-2023
Publisher: Elsevier BV
Date: 05-2007
DOI: 10.1111/J.1600-6143.2007.01796.X
Abstract: Adoptive immunotherapy using autologous Epstein-Barr virus (EBV)-specific cytotoxic T-lymphocytes (auto-CTL) can regress posttransplant lymphoproliferative disorders (PTLD). Widespread applicability of auto-CTL remains constrained. Generation is time-consuming, and auto-CTL cannot be established in patients treated with the B-cell depleting antibody rituximab. By contrast, pregenerated allogeneic CTL (allo-CTL) offers immediate accessibility. Allo-CTL has previously shown efficacy in "early" polyclonal- PTLD. We treated three patients with aggressive, advanced monoclonal-PTLD following solid-organ transplantation. All were refractory to at least three prior therapies. Despite HLA disparity, there was negligible toxicity, with early in vivo antiviral efficacy and reconstitution of EBV peptide-specific immunity. Two patients attained complete remission (CR). One remains in CR 17 months following therapy, coincident with persistence of donor-derived tumor targeted EBV-specific CTL the other died of non-PTLD related pathology. In the third patient, autopsy demonstrated homing of allo-CTL at the tumor site. Larger prospective studies of EBV-specific allo-CTL in PTLD are warranted.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1111/J.1600-6143.2011.03499.X
Abstract: Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of major, life-threatening lymphoproliferative diseases occurring in the post-transplant setting. The majority of PTLD is of B-cell origin and is associated with several risk factors, the most significant being Epstein-Barr virus (EBV) infection. EBV's in vitro transforming abilities, distinctive latency, clonality within the malignant cells and response to targeted therapies implicate a critical role in the biology of PTLD. This minireview focuses on EBV-related PTLD pathogenesis, in particular the interplay between aspects of the EBV life cycle and latency with nonviral factors resulting in the wide spectrum of histology and clinical presentations encountered in PTLD. With the increased prevalence of transplantation a rise in the incidence of PTLD may be expected. Therefore the importance of laboratory and animal models in the understanding of PTLD and the development of novel therapeutic approaches is discussed.
Publisher: American Society of Hematology
Date: 15-08-2007
DOI: 10.1182/BLOOD-2006-12-063008
Abstract: We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)–specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV-positive posttransplantation lymphoproliferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects of CTL infusions were observed and the response rate (complete or partial) in 33 patients was 64% at 5 weeks and 52% at 6 months. Fourteen patients achieved a complete remission, 3 showed a partial response, and 16 had no response at 6 months (5 died before completing treatment). At 5 weeks, there was a significant trend toward better responses with higher numbers of CD4+ cells in infused CTL lines (P = .001) that were maintained at 6 months (P = .001). Patients receiving CTLs with closer HLA matching responded better at 6 months (P = .048). Female patients responded better than male patients, but the differences were not statistically significant. Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for in idual patients. The response rate in this poor prognosis patient group is encouraging.
Publisher: American Society of Hematology
Date: 30-09-2010
DOI: 10.1182/BLOOD-2010-03-274076
Abstract: Immunosuppression resulting in impaired Epstein-Barr virus (EBV)–specific T-cell immunity is involved in the pathogenesis of EBV-positive post-transplantation lymphoproliferative disorder (EBV+ PTLD). Restoration of EBV-specific T-cell immunity by adoptive immunotherapy can induce remission. EBV-nuclear antigen-1 (EBNA1) is unique in being expressed in all cases of EBV+ PTLD. Recent data demonstrate that EBNA1 is not immunologically silent and can be exploited as a T-cell target. There are no data on EBNA1-specific T cells in PTLD. EBNA1-specific T cells capable of proliferation, interferon-γ release, and CD107a/b degranulation were assayed in 14 EBV+ PTLD diagnostic blood s les and 19 healthy controls. EBNA1-specific CD4+ T cells predominated and were expanded in 10 of 14 patients and 19 of 19 controls. Although human leukocyte antigen class I alleles influenced the magnitude of the response, EBNA1-specific CD8+ effector T cells were successfully generated in 9 of 14 EBV+ PTLD patients and 16 of 19 controls. The majority of PTLD patients had a polymorphism in an EBNA1 epitope, and T-cell recognition was greatly enhanced when EBNA1 peptides derived from the polymorphic epitope were used. These results indicate that EBNA1-specific T cells should be included in adoptive immunotherapy for PTLD. Furthermore, expansion protocols should use antigenic sequences from relevant EBV strains.
Publisher: American Society for Clinical Investigation
Date: 02-04-2012
DOI: 10.1172/JCI58092
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487439.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 21-01-2009
Publisher: S. Karger AG
Date: 21-10-2022
DOI: 10.1159/000527631
Abstract: Here, we present a novel case of a patient with chronic lymphocytic leukemia (CLL) who received CTLA-4 and then PD-1 immune-checkpoint blockade (ICB) as treatment for concomitant metastatic melanoma. Whereas the metastatic melanoma was responsive to ICB, the CLL rapidly progressed (but responded to ICB cessation and ibrutinib). There were no new genetic mutational drivers to explain the altered clinical course. PD-1/PD-L1/PD-L2 and CTLA-4/CD80/CD86 expression was not increased in CLL B cells, CD8 sup + /sup or CD4 sup + /sup T-cell subsets, or monocytes. The patient’s CLL B cells demonstrated strikingly prolonged in vitro survival during PD-1 blockade, which was not observed in s les taken before or after ICB, or with other patients. To our knowledge, a discordant clinical course to ICB coupled with these biological features has not been reported in a patient with dual malignancies.
Publisher: Wiley
Date: 09-2000
DOI: 10.1046/J.1365-2141.2000.02218.X
Abstract: S-Methylation by thiopurine methyltransferase (TPMT) is an important route of metabolism for the thiopurine drugs. About one in 300 in iduals are homozygous for a TPMT mutation associated with very low enzyme activity and severe myelosuppression if treated with standard doses of drug. To validate the use of molecular genetic techniques for the detection of TPMT deficiency, we have determined red blood cell TPMT activity in 240 adult blood donors and 55 normal children. Genotype was determined by restriction fragment length analysis of polymerase chain reaction products in a cohort of 79 of the blood donors and five cases of azathioprine-induced myelosupression, and this confirmed a close relationship between genotype and phenotype. In 17 of the 24 cases in which mutations were found, DNA was also available from remission bone marrow. In one of these cases, DNA from the remission marrow s le indicated the presence of a non-mutated allele that had not been seen in the blast DNA s le obtained at presentation. These results indicate that polymerase chain reaction-based assays give reliable and robust results for the detection of TPMT deficiency, but that caution should be exercised in relying exclusively on DNA obtained from lymphoblasts in childhood leukaemia.
Publisher: Oxford University Press (OUP)
Date: 13-11-2015
DOI: 10.1111/CEI.12716
Abstract: In 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency-II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA-A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA-A*02– versus HLA-A*02+ EBV+cHL patients, suggesting that LMP2A-specific CD8+ T cell anti-tumoral immunity may be relatively ineffective in HLA-A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen-specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex-vivo LMP1/2A-specific CD8+ T cell responses was elevated in HLA-A*02+ patients. Furthermore, in a controlled in-vitro assay, LMP2A-specific CD8+ T cells from healthy HLA-A*02 heterozygotes expanded to a greater extent with HLA-A*02-restricted compared to non-HLA-A*02-restricted cell lines. In an extensive analysis of HLA class I-restricted immunity, immunodominant EBNA3A/3B/3C-specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A-specific responses were confined largely to HLA-A*02. Our results demonstrate that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8+ T cell response than non-HLA-A*02 alleles, an effect confined to EBV latency-II antigens. Thus, the protective effect of HLA-A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency-II antigen-specific CD8+ T cell hierarchies.
Publisher: Future Medicine Ltd
Date: 12-2011
DOI: 10.2217/IMT.11.135
Abstract: Evaluation of: Savoldo B, Ramos CA, Liu E et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121(5), 1822–1826 (2011). Chimeric antigen receptor (CAR)-T cells are promising antitumor immunotherapies. However, there are limited reports of persistence, tumor-homing and clinical efficacy in cancer patients. Savoldo and colleagues used a novel approach to compare the use of first- and second-generation tumor-specific CAR-T cells in six B-cell lymphoma patients. They provide one of the first comparisons in human subjects and demonstrate the superiority of second-generation CAR-T cells to expand, survive and home to the tumor site.
Publisher: Wiley
Date: 23-01-2013
DOI: 10.1002/GCC.22044
Abstract: We employed a Hidden-Markov-Model (HMM) algorithm in loss of heterozygosity (LOH) analysis of high-density single nucleotide polymorphism (SNP) array data from Non-Hodgkin's lymphoma (NHL) entities, follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). This revealed a high frequency of LOH over the chromosomal region 11p11.2, containing the gene encoding the protein tyrosine phosphatase receptor type J (PTPRJ). Although PTPRJ regulates components of key survival pathways in B-cells (i.e., BCR, MAPK, and PI3K signaling), its role in B-cell development is poorly understood. LOH of PTPRJ has been described in several types of cancer but not in any hematological malignancy. Interestingly, FL cases with LOH exhibited down-regulation of PTPRJ, in contrast no significant variation of expression was shown in DLBCLs. In addition, sequence screening in Exons 5 and 13 of PTPRJ identified the G973A (rs2270993), T1054C (rs2270992), A1182C (rs1566734), and G2971C (rs4752904) coding SNPs (cSNPs). The A1182 allele was significantly more frequent in FLs and in NHLs with LOH. Significant over-representation of the C1054 (rs2270992) and the C2971 (rs4752904) alleles were also observed in LOH cases. A haplotype analysis also revealed a significant lower frequency of haplotype GTCG in NHL cases, but it was only detected in cases with retention. Conversely, haplotype GCAC was over-representated in cases with LOH. Altogether, these results indicate that the inactivation of PTPRJ may be a common lymphomagenic mechanism in these NHL subtypes and that haplotypes in PTPRJ gene may play a role in susceptibility to NHL, by affecting activation of PTPRJ in these B-cell lymphomas.
Publisher: Wiley
Date: 27-12-2011
DOI: 10.1002/AJH.22252
Abstract: Recently, nontumor specific circulating DNA was shown to be elevated in a broad range of lymphomas, implicating a role as a potential biomarker. Epstein-Barr virus' (EBV) presence within a proportion of lymphomas implies EBV-DNA has potential as a lymphoma-specific disease response biomarker. However, application would be restricted to EBV-associated lymphomas. Neither detailed comparison has been performed of lymphoma-specific versus nonspecific DNA as disease response biomarkers nor have the kinetics of circulating DNA during treatment been established, and the optimal methodology remains unknown. We prospectively evaluated DNA levels and clinical response of 63 lymphoma patients. DNA was measured in paired serum, plasma, and cell s les at five predetermined time-points taken prior, during and following treatment. Both cell-free (c-f) circulating EBV-DNA (in EBV-associated lymphoma) and nonspecific c-f DNA levels (in all lymphomas) were elevated and discriminatory at presentation compared to healthy controls. Nonspecific c-f DNA was significantly associated with baseline serum lactate dehydrogenase. Within EBV-associated lymphomas at presentation, there was a strong correlation between specific and nonspecific circulating c-f DNA (r = 0.9, P < 0.0001). However, only c-f EBV-DNA correlated with clinical/radiological response. In addition, c-f EBV-DNA, and not nonspecific c-f DNA, provided an early marker of relapsed and refractory disease. Serum versus plasma, and single versus multiple-copy EBV-gene targets were equivalent. Lymphoma-specific DNA is a disease response biomarker however, nonspecific DNA reflected neither lymphoma-specific DNA nor therapeutic response. Lymphoma disease response can be monitored by blood tests, but new lymphoma-specific biomarkers need to be identified to broaden applicability.
Publisher: Elsevier BV
Date: 03-0003
Publisher: Wiley
Date: 14-10-2020
DOI: 10.1002/JHA2.116
Publisher: Wiley
Date: 10-2012
DOI: 10.1111/J.1445-5994.2011.02587.X
Abstract: Recent reports suggest genetic polymorphisms influence susceptibility to rituximab-induced late-onset neutropenia (LON), which in turn may be a predictor of good outcome in B-cell lymphoma. We report the largest study to date assessing FCGR3A-V158F polymorphisms in diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide/hydroxydaunorubicin/Oncovin (vincristine) rednisone/rituximab (CHOP-R). The influence of C1qA-A276G polymorphisms in DLBCL, and the impact of both polymorphisms on susceptibility to LON and outcome were also examined. 115 DLBCL patients treated with CHOP-R were compared with 105 healthy White people controls with regards to FCGR3A-V158F and C1qA-A276G polymorphisms. LON incidence and event-free and overall survival (EFS and OS) were analysed for linkage to either polymorphism. The FCGR3A-V158F but not the C1qA-A276G polymorphism influenced the risk of developing LON. 50% of FCGR3A-158V/V patients experienced LON. In contrast, only 7% V/F and 2% F/F experienced LON. The FCGR3A-158V/V genotype was associated with LON compared with V/F (P = 0.028) and F/F genotypes (P = 0.005). Although no patients with either LON or FCGR3A-158V homozygosity relapsed compared with 33% FCGR3A-158F/F and 21% non-LON, this did not translate into improved EFS or OS. Polymorphic analysis may be a predictive tool to identify those at high risk of LON. Prospective studies are required to establish definitively if LON or FCGR3A-158V/V genotype influences outcome.
Publisher: Informa UK Limited
Date: 09-07-2012
Publisher: Cold Spring Harbor Laboratory
Date: 19-06-2019
DOI: 10.1101/674259
Abstract: B-cell non-Hodgkin’s lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than in idual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2006
DOI: 10.1158/1078-0432.CCR-05-2008
Abstract: Purpose: Latent Epstein-Barr virus (EBV) genomes are found in the malignant cells of approximately one-third of Hodgkin's lymphoma (HL) cases. Detection and quantitation of EBV viral DNA could potentially be used as a biomarker of disease activity. Experimental Design: Initially, EBV-DNA viral load was prospectively monitored from peripheral blood mononuclear cells (PBMC) in patients with HL. Subsequently, we analyzed viral load in plasma from a second cohort of patients. A total of 58 patients with HL (31 newly diagnosed, 6 relapsed, and 21 in long-term remission) were tested. Using real-time PCR, 43 PBMC and 52 plasma s les were analyzed. Results: EBV-DNA was detectable in the plasma of all EBV-positive patients with HL prior to therapy. However, viral DNA was undetectable following therapy in responding patients (P = 0.0156), EBV-positive HL patients in long-term remission (P = 0.0011), and in all patients with EBV-negative HL (P = 0.0238). Conversely, there was no association seen for the EBV-DNA load measured from PBMC in patients with active EBV-positive HL patients as compared with EBV-negative HL, or patients in long-term remission. EBV-DNA load in matched plasma/PBMC s les were not correlated. Conclusions: We show that free plasma EBV-DNA has excellent sensitivity and specificity, and can be used as a noninvasive biomarker for EBV-positive HL and that serial monitoring could predict response to therapy. Additional prospective studies are required to further evaluate the use of free plasma EBV-DNA as a biomarker for monitoring response to treatment in patients with EBV-positive HL.
Publisher: Elsevier BV
Date: 12-2004
Publisher: Wiley
Date: 28-06-1993
DOI: 10.1111/J.1365-2257.1993.TB00138.X
Abstract: The Blood Transfusion Service introduced screening for Hepatitis C antibody (HCV) in September 1991. This is done by second generation enzyme linked immunosorbent assay (ELISA) tests. We present a case of post-transfusion hepatitis C hepatitis in a patient with myeloma. Infection was acquired before screening was introduced. Both the patient and the infected blood donor were diagnosed using ELISA assays and the polymerase chain reaction (PCR). In this way we prevented the blood donor from spreading the virus via subsequent blood donations. There were some interesting discrepancies in the HCV assays. Blood s les, when tested by different methods, gave both positive and negative results. The results also varied according to when the blood s les to be tested were taken. The case illustrates the importance of confirming positive results and that no single laboratory test is entirely satisfactory in diagnosing HCV infection.
Publisher: Informa UK Limited
Date: 08-10-2016
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.LEUKRES.2009.05.004
Abstract: FOXP1 is a transcriptional repressor that has been proposed to repress the expression of some NFkappaB-responsive genes. Furthermore, truncated forms of FOXP1 have been associated with a subtype of Diffuse Large B-cell Lymphoma characterised by constitutive NFkappaB activity, indicating that they may inhibit this repression. We have shown that FL tumors have increased relative abundance of truncated FOXP1 isoforms and this is associated with increased expression of NFkappaB-associated genes. Our results provide strong evidence that relative FOXP1 isoform abundance is associated with NFkappaB activity in FL, and could potentially be used as a marker for this gene signature.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6532518.V1
Abstract: AbstractPurpose: In a i ost hoc /i analysis of the CATNON trial (NCT00626990), we explored whether adding temozolomide to radiotherapy improves outcome in patients with i IDH1/2 /i wildtype (wt) anaplastic astrocytomas with molecular features of glioblastoma [redesignated as glioblastoma, isocitrate dehydrogenase–wildtype ( i IDH /i -wt) in the 2021 World Health Organization (WHO) classification of central nervous system tumors]. Patients and Methods: From the randomized phase III CATNON study examining the addition of adjuvant and concurrent temozolomide to radiotherapy in anaplastic astrocytomas, we selected a subgroup of i IDH1/2 /i wt and i H3F3A /i wt tumors with presence of i TERT /i promoter mutations and/or i EGFR /i lifications and/or combined gain of chromosome 7 and loss of chromosome 10. Molecular abnormalities including i MGMT /i promoter methylation status were determined by next-generation sequencing, DNA methylation profiling, and SNaPshot analysis. Results: Of the 751 patients entered in the CATNON study, 670 had fully molecularly characterized tumors. A total of 159 of these tumors met the WHO 2021 molecular criteria for glioblastoma, i IDH /i -wt. Of these patients, 47 received radiotherapy only and 112 received a combination of radiotherapy and temozolomide. There was no added effect of temozolomide on either overall survival [HR, 1.19 95% confidence interval (CI), 0.82–1.71] or progression-free survival (HR, 0.87 95% CI, 0.61–1.24). i MGMT /i promoter methylation was prognostic for overall survival, but was not predictive for outcome to temozolomide treatment either with respect to overall survival or progression-free survival. Conclusions: In this cohort of patients with glioblastoma, i IDH /i -wt temozolomide treatment did not add benefit beyond that observed from radiotherapy, regardless of i MGMT /i promoter status. These findings require a new well-powered prospective clinical study to explore the efficacy of temozolomide treatment in this patient population. /
Publisher: Wiley
Date: 28-04-2003
DOI: 10.1046/J.1365-2141.2003.04303.X
Abstract: Reduced bone mineral density (BMD) has been reported following allogeneic stem cell transplantation (alloSCT) but the effects of autologous SCT (autoSCT) are less well characterized. We performed a prospective study of BMD changes and its determinants in 44 SCT recipients (38 auto and six allo 30 peripheral blood SCT and 14 bone marrow transplantation). Serial measurements of BMD at the lumbar spine and femoral neck were performed at baseline and at 3, 6, 12 and 24 months, and spinal radiographs were performed at baseline and 12 months. Mean baseline BMD values at the femoral neck and spine were within normal limits. At 3 months, there was a significant decline of BMD at the femoral neck (P = 0.011) and a non-significant trend towards reduction at the spine. BMD loss persisted for up to 2 years at the femoral neck (P = 0.005), but values returned to baseline at the spine. Reflecting the rapid initial decline in BMD, bone-specific alkaline phosphatase (a serum marker of bone formation) showed a significant initial decline at 1 month but had recovered to pretransplant levels by 3 months. No new fractures were detected at 1 year post transplant. Sex, diagnosis, use of total body irradiation, stem cell source and type of graft (auto versus allo) did not significantly predict BMD change over the first 12 months. In conclusion, significant and persistent bone loss at the femoral neck was demonstrated in this group of patients following stem cell transplantation. The implications of these findings for future fracture risk require further study.
Publisher: Wiley
Date: 05-03-2013
DOI: 10.1002/AJH.23398
Abstract: Despite the Revised International Prognostic Index's (R-IPI) undoubted utility in diffuse large B-cell lymphoma (DLBCL), significant clinical heterogeneity within R-IPI categories persists. Emerging evidence indicates that circulating host immunity is a robust and R-IPI independent prognosticator, most likely reflecting the immune status of the intratumoral microenvironment. We hypothesized that direct quantification of immunity within lymphomatous tissue would better permit stratification within R-IPI categories. We analyzed 122 newly diagnosed consecutive DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemo-immunotherapy. Median follow-up was 4 years. As expected, the R-IPI was a significant predictor of outcome with 5-year overall survival (OS) 87% for very good, 87% for good, and 51% for poor-risk R-IPI scores (P < 0.001). Consistent with previous reports, systemic immunity also predicted outcome (86% OS for high lymphocyte to monocyte ratio [LMR], versus 63% with low LMR, P = 0.01). Multivariate analysis confirmed LMR as independently prognostic. Flow cytometry on fresh diagnostic lymphoma tissue, identified CD4(+) T-cell infiltration as the most significant predictor of outcome with ≥23% infiltration iding the cohort into high and low risk groups with regard to event-free survival (EFS, P = 0.007) and OS (P = 0.003). EFS and OS were independent of the R-IPI and LMR. Importantly, within very good/good R-IPI patients, CD4(+) T-cells still distinguished patients with different 5 year OS (high 96% versus low 63%, P = 0.02). These results illustrate the importance of circulating and local intratumoral immunity in DLBCL treated with R-CHOP.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1111/AJT.16628
Abstract: Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation rocessing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).
Publisher: Wiley
Date: 11-07-2014
DOI: 10.1111/BJH.13029
Abstract: The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 10(9) /l and ≤50 × 10(9) /l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR platelet count >150 × 10(9) /l) or partial response (PR platelet count >50 × 10(9) /l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR platelet count >30 × 10(9) /l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m(2) four-dose schedule in relapsed/chronic ITP.
Publisher: American Society of Hematology
Date: 30-09-2019
DOI: 10.1182/BLOODADVANCES.2019000458
Abstract: Practices in early-stage FL are variable and include radiation alone, systemic therapy, CMT, or observation. Each practice resulted in similar excellent outcomes randomized trials are required to determine the optimal treatment.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S0268-960X(03)00028-6
Abstract: The herpesvirus Human Cytomegalovirus (HCMV) is an important opportunistic infection in recipients of allogeneic haemopoietic stem cell transplants, in whom HCMV-specific CD8+ and CD4+ T-cell responses are impaired. The nature of the HCMV-specific T-cell response in healthy virus carriers has been characterised in detail. High frequencies of circulating CD8+ T-cells that recognise defined viral peptides are maintained for years, and include in idual CD8+ clones that have undergone extensive clonal expansion and phenotypic ersification in vivo. Following stem cell transplantation, the kinetics of HCMV-specific CD8+ T-cell reconstitution in the recipient are related to the presence or absence of antigen-experienced CD8+ T-cells transferred via the allograft, and to the presence of the virus in the recipient. We discuss recent progress in our understanding of HCMV-specific immunity in healthy virus carriers and in recipients after alloSCT.
Publisher: American Society of Hematology
Date: 08-04-2020
DOI: 10.1182/BLOODADVANCES.2019001390
Abstract: Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P & .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators.
Publisher: Springer Science and Business Media LLC
Date: 22-12-1999
Abstract: We analysed 57 patients with non-myeloid malignancies who received a non-purged autologous PBSCT. All had similar mobilisation and conditioning regimens. A high prior chemotherapy score and the number of chemotherapy lines used (P = 0.015 and P = 0.01, respectively) were adverse predictors of CD34 cell yields. Lower CD34 values (P = 0.002) were seen in patients treated with potent stem cell toxins (BCNU, melphalan, CCNU and mustine), designated toxicity factor 4 agents (TF4). All patients infused with grafts containing CD34 cell doses between 1.0 and 2.0 x 10(6)/kg (range 1.25-1.90) engrafted by day 51. The only variable associated with slow platelet recovery was exposure to TF4 (P = 0.007). The majority of patients with CD34 >1.0 x 10(6)/kg achieved rapid and sustained engraftment and the only predictive factor of delayed recovery is prior exposure to stem cell toxins. Potential PBSCT candidates should if possible avoid first line and salvage chemotherapy containing TF4 drugs. We therefore advocate a minimum CD34 threshold of >1.0 x 10(6)/kg in patients without extensive prior chemoradiotherapy, and > or = 2.0 x 10(6)/kg in all other patients.
Publisher: Hindawi Limited
Date: 2014
DOI: 10.1155/2014/264723
Abstract: We retrospectively analyzed the p.V158F polymorphism of Fc γ -receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548 ). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.BLRE.2004.09.001
Abstract: Follicular lymphoma (FL) is a malignancy of follicle centre B cells that have at least a partially follicular pattern, and is the commonest type of indolent Non-Hodgkin's lymphoma. Except in the subset of patients with localized disease, FL should still be regarded as an incurable malignancy with a relentless relapsing/remitting course. However, the provocative new data covered by this review (including anti-CD20 antibody therapy, BCL-2, radioimmunotherapy, new chemotherapeutic agents and anti-idiotype vaccination), provides much cause for excitement and guarded optimism. Rituximab represents a novel treatment approach for a variety of disease settings, with a proven excellent efficacy and toxicity profile. Long-term data is required to establish whether its use translates into survival benefit. As the clinical activity of rituximab and other new therapeutic approaches becomes established, it will be important to determine how best to integrate these results into the standard care of patients with follicular lymphoma.
Publisher: Springer Netherlands
Date: 2015
Publisher: The American Association of Immunologists
Date: 10-2006
DOI: 10.4049/JIMMUNOL.177.7.4897
Abstract: Recent studies on Hodgkin’s lymphoma (HL) have indicated that patients with active disease display functional impairment of Ag-specific CD8+ T cells due to expansion of regulatory T cells at sites of disease and in the peripheral blood. Adoptive cellular immunotherapy based on EBV-specific CD8+ T cells has been explored with limited success to date. It has been proposed that improved targeting of these CD8+ T cells toward viral Ags that are expressed in HL may enhance future therapeutic vaccine strategies. In this study, we have developed a novel replication-deficient adenoviral Ag presentation system that is designed to encode glycine alanine repeat-deleted EBV nuclear Ag 1 covalently linked to multiple CD8+ T cell epitopes from latent membrane proteins 1 and 2. A single stimulation of CD8+ T cells from healthy virus carriers, and patients with HL with this adenoviral construct in combination with IL-2, was sufficient to reverse the functional T cell impairment and restored both IFN-γ production and cytolytic function. More importantly, these activated CD8+ T cells responded to tumor cells expressing membrane proteins and recognized novel EBNA1 epitopes. Flow cytometric analysis revealed that a large proportion of T cells expanded from patients with HL were CD62Lhigh and CD27high, and CCR7low, consistent with early to mid effector T cells. These findings provide an important platform for translation of Ag-specific adoptive immunotherapy for the treatment of EBV-associated malignancies such as HL and nasopharyngeal carcinoma.
Publisher: Elsevier BV
Date: 10-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-01-2013
DOI: 10.1158/1078-0432.CCR-12-2693
Abstract: Purpose: Candidate circulating disease response biomarkers for classical Hodgkin lymphoma (cHL) might arise from Hodgkin–Reed–Sternberg (HRS) cells or nonmalignant tumor-infiltrating cells. HRS cells are sparse within the diseased node, whereas benign CD163+ M2 tissue-associated macrophages (TAM) are prominent. CD163+ cells within the malignant node may be prognostic, but there is no data on serum CD163 (sCD163). The HRS-specific serum protein sTARC shows promise as a disease response biomarker. Tumor-specific and tumor-infiltrating circulating biomarkers have not been compared previously. Experimental Design: We prospectively measured sCD163 and sTARC in 221 s les from 47 patients with Hodgkin lymphoma and 21 healthy participants. Blood was taken at five fixed time-points prior, during, and after first-line therapy. Results were compared with radiological assessment and plasma Epstein-Barr virus DNA (EBV-DNA). Potential sources of circulating CD163 were investigated, along with immunosuppressive properties of CD163. Results: Pretherapy, both sCD163 and sTARC were markedly elevated compared with healthy and complete remission s les. sCD163 better reflected tumor burden during therapy, whereas sTARC had greater value upon completion of therapy. sCD163 correlated with plasma EBV-DNA, and associated with B symptoms, stage, and lymphopenia. Circulating CD163+ monocytes were elevated in patients, indicating that sCD163 are likely derived from circulating and intratumoral cells. Depletion of cHL CD163+ monocytes markedly enhanced T-cell proliferation, implicating monocytes and/or TAMs as potential novel targets for immunotherapeutic manipulation. Conclusion: The combination of circulating tumor-infiltrate (sCD163) and tumor-specific (sTARC) proteins is more informative than either marker alone as disease response biomarkers in early and advanced disease during first-line therapy for cHL. Clin Cancer Res 19(3) 731–42. ©2012 AACR.
Publisher: Wiley
Date: 16-07-2020
DOI: 10.1111/BJH.16946
Publisher: Oxford University Press (OUP)
Date: 15-03-2010
DOI: 10.1086/650007
Abstract: We describe a unique case of fulminant infectious mononucleosis and recurrent Epstein-Barr virus reactivation presenting in an adolescent. Detailed assays of Epstein-Barr virus-specific T cell immunity revealed defects in the patient's T cell receptor signalling pathway characterized by a lack of interleukin-2 and CD25 expression, which may have contributed to her clinical course. Allogeneic stem cell transplantation reversed the clinical and laboratory phenotype.
Publisher: Springer Science and Business Media LLC
Date: 08-1999
Abstract: Following ASCT for multiple myeloma, it is unclear whether relapse is due solely to the presence of residual myeloma cells after myeloablation, or whether it is in part attributable to contamination of the stem cell harvest with viable malignant cells. Positive selection of CD34+ cells markedly reduces plasma cell contamination. We performed a case controlled analysis in which 15 patients with myeloma who underwent autologous PBSCT with CD34+cell selection using the Ceprate System (index group), were compared with 15 matched controls. All subjects received an identical preparative regimen. The median times to neutrophils >/=0.5 x 10(9)/l and unsupported platelets >/=50 x 10(9)/l were 14 and 23 days for the CD34+cell selected group and 11 (P = 0.03) and 14 (P = 0.029) for the case controls. Median follow-up of purged patients from autologous PBSCT was 32 months (range 18-43). At 36 months, the probability of PFS was 47 +/- 14% and 46 +/- 14% in the index and control groups (P = 0.44). The 3 year probability of OS was 69 +/- 13% for the CD34+ cell selected arm and 66 +/- 12.4% in unpurged patients (P = 0.91). Median PFS for the cell selected group is 24 months (CI 19.1-36.0), and 29 months for controls (CI 7.1-50.9). Eleven patients undergoing cell selection remain alive, seven of whom are progression free. At the same time-point after unpurged autologous PBSCT, the corresponding figures are 12 patients alive, with seven remaining progression free. Autologous PBSCT with CD34+ cell selection is both feasible and safe, but results in delayed engraftment as compared to case controls. The 3 year probability of PFS and OS in the cell selected arm was similar to that of the unpurged controls. Our findings indicate that autologous PBSCT with CD34+ cell selection appears not to have any favourable effect on disease progression. However, the results of this case controlled analysis should be cautiously interpreted, and the role of CD34+ selection in autologous PBSCT should be further investigated by large randomised trials.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JVIROMET.2012.05.005
Abstract: Epstein-Barr virus (EBV) is implicated in a range of B-cell malignancies and expresses unique microRNAs (EBV-miRNAs). Due to the requirements for high-quality RNA, studies profiling EBV-miRNA in EBV-positive lymphomas have been restricted to cell-lines or frozen s les. However, the most commonly available archived patient material is paraffin-embedded formalin-fixed (FFPE) tissue. This has impeded the widespread profiling of EBV-miRNA expression in clinical s les. The requirements for accurate EBV-miRNA real-time RT-PCR quantitation in FFPE tissues representing a broad-spectrum of EBV-positive lymphomas were determined systematically, including where the neoplastic cells are sparse relative to the non-malignant infiltrate. The level of cellular EBV-load correlated strongly with the sum of EBV-miRNA expression and the number of EBV-miRNAs detectable. As calibrators for cellular EBV-load, the sum EBV-miRNA was optimal to EBV-genome copy number and EBER2 expression level, with the added advantage of not requiring additional assays. EBV-miRNA was profiled reliably within archival FFPE tissue in 14/23 patients, but not in tissues with low abundance EBV. This method enabled specific and simultaneous detection of numerous EBV-miRNAs in FFPE lymphoma s les that contain EBV at high to medium levels, making it as a useful tool for studies of EBV-miRNA in the majority of diagnostic biopsies.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2018
DOI: 10.1038/S41467-018-07214-W
Abstract: Epigenetic reprogramming in cancer genomes creates a distinct methylation landscape encompassing clustered methylation at regulatory regions separated by large intergenic tracks of hypomethylated regions. This methylation landscape that we referred to as Methylscape is displayed by most cancer types, thus may serve as a universal cancer biomarker. To-date most research has focused on the biological consequences of DNA Methylscape changes whereas its impact on DNA physicochemical properties remains unexplored. Herein, we examine the effect of levels and genomic distribution of methylcytosines on the physicochemical properties of DNA to detect the Methylscape biomarker. We find that DNA polymeric behaviour is strongly affected by differential patterning of methylcytosine, leading to fundamental differences in DNA solvation and DNA-gold affinity between cancerous and normal genomes. We exploit these Methylscape differences to develop simple, highly sensitive and selective electrochemical or colorimetric one-step assays for the detection of cancer. These assays are quick, i.e., analysis time ≤10 minutes, and require minimal s le preparation and small DNA input.
Publisher: Wiley
Date: 24-07-2019
DOI: 10.1111/EJH.13274
Abstract: Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV ‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV ‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV ‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME). We used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL. Incidence of EBV ‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV ‐neg DLBCL ( P = 0.018). EBV ‐pos tissues had similar expression of T‐cell genes compared to EBV ‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 “M2” macrophage score. In EBV ‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.
Publisher: The American Association of Immunologists
Date: 06-2002
DOI: 10.4049/JIMMUNOL.168.11.5455
Abstract: Human CMV (HCMV) infection provides an informative model of how long term human CD8+ T cell memory is maintained in the presence of Ag. To clarify the phenotypic identity of Ag-experienced human CD8+ T cells in vivo, we determined the expression of costimulation and chemokine receptors on Ag-specific CD8+ T cells by quantifying in idual virus-specific clones in different cell populations using TCR clonotypic probing. In healthy HCMV carriers, expanded CD8+ clones specific for either HCMV tegument protein pp65 or immediate-early protein IE72 are found in both CD45ROhigh cells and the subpopulation of CD45RAhigh cells that lack the costimulatory molecule CD28. In contrast to previous suggested models of CD8+ T cell memory, we found that in healthy virus carriers highly purified CD28−CD45RAhighCCR7− cells are not terminally differentiated, because following stimulation in vitro with specific HCMV peptide these cells underwent sustained clonal proliferation, up-regulated CD45RO and CCR5, and showed strong peptide-specific cytotoxic activity. In an in idual with acute primary HCMV infection, HCMV pp65-specific CD8+ T cells are predominantly CD28−CD45ROhighCCR7−. During convalescence, an increasing proportion of pp65-specific CD8+ T cells were CD28−CD45RAhighCCR7−. We conclude that naive human CD8+ T cells are CD28+CD45RAhigh, express CCR7 but not CCR6, and are predominantly CD27+ and L-selectin CD62 ligand-positive. The phenotype CD27+CD45RAhigh should not be used to identify naive human CD8+ T cells, because CD27+CD45RAhigh cells also contain a significant subpopulation of CD28−CD27+ Ag-experienced expanded clones. Thus CD8+ T cell memory to HCMV is maintained by cells of expanded HCMV-specific clones that show heterogeneity of activation state and costimulation molecular expression within both CD45ROhigh and CD28−CD45RAhigh T cell pools.
Publisher: Elsevier BV
Date: 05-2009
DOI: 10.1016/J.LEUKRES.2008.09.007
Abstract: The t(14 )(q21 q34) BCL2 translocation is a common genetic alteration in follicular and diffuse large B-cell lymphoma. However, it is not invariably associated with BCL2 gene overexpression due to undefined mechanisms that regulate expression from the proximal immunoglobulin heavy-chain (IgH) promoter. The BACH2 transcriptional repressor is able to modulate activity of this promoter. Here we have shown that, in tumor s les with BCL2 translocation, those with high levels of BACH2 had significantly lower BCL2 transcript abundance compared to those with low levels of BACH2. This indicates that BACH2 may be partially responsible for regulation of BCL2 expression from the t(14 )(q21 q34) translocation.
Publisher: Springer Science and Business Media LLC
Date: 08-04-2020
Publisher: Informa UK Limited
Date: 2009
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10428190600649562
Abstract: To our knowledge, there has been no report of spontaneous regression in a non-immunocompromised adult with classical Hodgkin's lymphoma (HL) in the absence of chemotherapy. We describe spontaneous regression and subsequent relapse of Epstein - Barr virus (EBV)-positive HL in an otherwise healthy male adult. The clinical course was associated with an increase in regulatory T-cell markers within the peripheral blood and diseased lymph node at the time of relapse and with a concomitant reduction in cellular immunity against relevant EBV latent membrane protein tumor-associated antigens. Our findings are in keeping with previous observations that implicate impaired cellular immunity in the immunopathogenesis of EBV-positive HL.
Publisher: Wiley
Date: 08-02-2011
DOI: 10.1002/GCC.20856
Abstract: Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non-Hodgkin's lymphoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By integrating genome-wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including lification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, lification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA-mediated knock-down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic lification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy.
Publisher: American Society of Hematology
Date: 27-05-2021
Publisher: American Society of Hematology
Date: 11-06-2015
DOI: 10.1182/BLOOD-2015-03-635169
Abstract: DLBCL can be detected in the blood by immunoglobulin high-throughput sequencing (Ig-HTS) with high specificity. Although DLBCL can be detected in leukocytes or plasma by Ig-HTS, plasma has greater sensitivity and more accurately reflects disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487433.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487421
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Springer Science and Business Media LLC
Date: 03-2005
DOI: 10.1038/NCPONC0107
Abstract: The Epstein-Barr virus (EBV) is uniquely associated with a broad range of human malignancies. In spite of their erse cellular origin, most of these malignancies share common features, including the expression of either some or all of the EBV latent proteins, which can be potentially exploited for immune-based therapies. Here we discuss new and emerging strategies to manipulate the immune response to specifically boost T-cell immunity towards viral proteins that are expressed in EBV-associated malignancies. These strategies are used either alone or as an adjuvant therapy in combination with chemotherapy and/or monoclonal antibodies. Overall, this strategy may serve as a new paradigm for the successful multi-modality treatment of malignancies.
Publisher: American Society of Hematology
Date: 15-08-2007
DOI: 10.1182/BLOOD-2007-01-066100
Abstract: In Hodgkin lymphoma (HL), the malignant Hodgkin Reed-Sternberg cells interact with the host microenvironment to create an immunosuppressive network that protects the lymphoma from immune attack. These mechanisms are not fully understood. We examined the role of the immunomodulatory protein galectin-1 (Gal-1) on Epstein-Barr virus-specific CD8+ T cell responses in HL. Initial studies indicated Gal-1 expression in all in vitro established Hodgkin Reed-Sternberg cell lines. In situ analysis revealed Gal-1 expression in 26 of 42 classic HL, whereas Gal-1 was uniformly negative in nodular lymphocyte predominant HL. Gal-1hi expression was associated with male gender, older patients, reduced CD8+ T cell infiltration at the tumor site, and most importantly, an impaired latent membrane protein 1 and 2-specific CD8+ T-cell responses. In vitro exposure to recombinant Gal-1 inhibited proliferation and interferon-γ expression by Epstein-Barr virus-specific T cells. These observations provide an important link between the Gal-1-mediated immunomodulatory networks and loss of antigen-specific T-cell function in classic HL.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 10-11-2017
Publisher: Impact Journals, LLC
Date: 04-05-2018
Publisher: American Society of Hematology
Date: 05-06-2019
DOI: 10.1182/BLOODADVANCES.2018030676
Abstract: Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell ersity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56dim NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56bright and CD56dimDNAM-1pos NK cell subsets, CD56dimDNAM-1neg NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56dimDNAM-1neg NK cells impaired CD56dimDNAM-1pos NK cell–mediated killing, indicating a potential inhibitory role for the CD56dimDNAM-1neg NK cell subset. Transcriptome analysis revealed that CD56dimDNAM-1neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56dimDNAM-1neg NK cells were found to differentiate from CD56dimDNAM-1pos NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56dimDNAM-1pos/CD56dimDNAM-1neg NK cell ratios and reduced cytotoxic activity of CD56dimDNAM-1pos NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell–targeting therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487427.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1351
Abstract: A erse intratumoral T‐cell receptor (TCR) repertoire is associated with improved survival in diffuse large B‐cell lymphoma (DLBCL) treated with rituximab/cyclophosphamide/doxorubicin rednisolone/vincristine (R‐CHOP) chemoimmunotherapy. We explored the impact of intratumoral TCR repertoire on interim PET (iPET) done after four cycles of R‐CHOP, the relationships between intratumoral and circulating repertoire, and the phenotypes of expanded clonotypes. We sequenced the third complementarity‐determining region of TCRβ in tumor s les, blood at pre‐therapy and after four cycles of R‐CHOP in 35 patients enrolled in ALLGNHL21 trial in high‐risk DLBCL. We correlated the TCR ersity metrics with iPET status, gene expression profiles and HLA‐class I genotypes. We then sequenced the FACS‐sorted peripheral blood T cells in six patients, and pentamer‐sorted EBV‐specific CD8 + T cells in one patient from this cohort. Compared with iPET − patients, the intratumoral TCR repertoire in iPET + patients was characterised by higher cumulative frequency of abundant clonotypes and higher productive clonality. There was a variable overlap between circulating and intratumoral repertoires, with the dominant intratumoral clonotypes more likely to be detected in the blood. The majority of shared clonotypes were CD8 + PD‐1 HI T cells, and CD8 + T cells had the largest clonal expansions in tumor and blood. In a patient with EBV + DLBCL, EBV‐specific intratumoral clonotypes were trackable in the blood. This study demonstrates that clonally expanded intratumoral TCR repertoires are associated with iPET + and that the blood can be used to track tumor‐associated antigen‐specific clonotypes. These findings assist the rationale design and therapeutic monitoring of immunotherapeutic strategies in DLBCL.
Publisher: Springer Science and Business Media LLC
Date: 08-1998
Abstract: Allogeneic peripheral blood progenitor cell transplantation (alloPBPCT) is increasingly used as an alternative to bone marrow transplantation (alloBMT). Early data suggest that the incidence and severity of acute graft-versus-host disease (GVHD) following alloPBPCT is no higher than that seen with alloBMT, despite the increased number of cytotoxic T cells infused with mobilised blood. We compared 12 patients undergoing alloPBPCT with 12 well-matched alloBMT controls. All patients received identical GVHD prophylaxis. No T cell depletion or CD34 purification was performed. Median engraftment times for neutrophils >0.5 x 10(9)/l and platelets >20 x 10(9)/l were 14 and 12 (alloPBPCT) and 21 and 23 days (alloBMT), respectively (P = 0.0035 and P = 0.002). There was no difference in antibiotic requirements (P = 0.83), platelet support (P = 0.59) or days in hospital (P = 0.51). After alloPBPCT, five patients developed > or =grade II acute GVHD vs five patients after alloBMT (P = 0.99). There was one death (alloBMT) at 100 days and three at 1 year (all due to relapse). There was one death at 100 days with alloPBPCT, and 11 patients remain alive (range 9-21 months) to date. Chronic GVHD occurred in five patients in the PBPC arm and one patient in the BM arm (P = 0.14). This case-controlled analysis indicates that alloPBPCT results in more rapid engraftment kinetics but in no significant difference in transplant-related morbidity or mortality. There is no difference in the incidence of acute GVHD. However, there is a trend towards increased incidence of chronic GVHD in patients allografted with PBPC. Prospective randomised trials are required to determine further the role of alloPBPCT.
Publisher: American Society of Hematology
Date: 18-03-2021
Abstract: Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting rocessing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 04-2021
DOI: 10.3324/HAEMATOL.2020.274258
Abstract: B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than in idual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.
Publisher: Wiley
Date: 28-06-1993
Publisher: Wiley
Date: 12-2016
DOI: 10.1111/IMJ.13051
Abstract: The majority of patients with Hodgkin lymphoma enjoy durable remissions following front-line treatment. This typically involves combination chemotherapy with or without radiotherapy. A significant minority of patients experience relapsed/refractory disease, of whom only approximately half can be 'salvaged' with conventional second-line treatments. Until recently, for those patients either failing or who are not fit for salvage, there have been few curative alternatives. Furthermore, there is a significant risk of delayed treatment complications to conventional therapies, including secondary malignancies and cardiac disease. However, novel targeted therapies are producing excellent results in clinical trials. They provide additional treatment options for those with relapsing/refractory disease they may have potential in front-line therapy. The anti-CD30 antibody brentuximab vedotin (BV) has been tested as monotherapy and in combination in a variety of clinical settings, including in relapsed/refractory patients and as consolidative therapy following standard second-line therapy. Nivolumab and pembrolizumab, currently used in other malignancies that are known to utilise the programmed death pathway for survival, have shown outstanding results when used as single agents in heavily pre-treated (including BV refractory) patients. In idualising and adapting a patient's treatment course, whether augmenting or rationalising therapy, based on an interim positron emission tomography/computed tomography response is an important strategy currently under exploration to minimise toxicity while maximising response. Further work is needed to explore clinical and biological factors associated with improved outcomes. Knowledge of these factors combined with the movement of novel therapies into the front-line setting will enable in idualised therapy to enhance clinical responses and minimise toxicities.
Publisher: Wiley
Date: 02-2010
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487430.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Wiley
Date: 24-10-2020
DOI: 10.1002/AJH.26016
Publisher: Royal College of Physicians
Date: 05-2005
Publisher: American Society of Hematology
Date: 26-10-2023
Abstract: Hematopoietic stem and progenitor cells (HSPCs) rely on a complex interplay of transcription factors (TFs) to regulate differentiation into mature blood cells. A heptad of TFs - FLI1, ERG, GATA2, RUNX1, TAL1, LYL1, LMO2 - bind regulatory elements in bulk CD34+ HSPCs. However, whether specific heptad-TF combinations have distinct roles in regulating hematopoietic differentiation remained unknown. We mapped genome-wide chromatin contacts (HiC, H3K27ac HiChIP), chromatin modifications (H3K4me3, H3K27ac, H3K27me3) and 10 TF binding profiles (the Heptad, PU.1, CTCF, and STAG2) in HSPC subsets (HSC-MPP, CMP, GMP, MEP) and found that TF occupancy and enhancer-promoter interactions varied significantly across cell types and were associated with cell-type-specific gene expression. Distinct regulatory elements were enriched with specific heptad-TF combinations, including stem-cell-specific elements with ERG, and myeloid- and erythroid-specific elements with combinations of FLI1, RUNX1, GATA2, TAL1, LYL1, and LMO2. Furthermore, heptad-occupied regions in HSPCs were subsequently bound by lineage-defining TFs such as PU.1 and GATA1, suggesting that heptad factors may prime regulatory elements for use in mature cell types. We also found that enhancers with cell-type-specific heptad occupancy shared a common grammar with respect to TF binding motifs, suggesting that combinatorial binding of specific TF complexes was at least partially regulated by features encoded in specific DNA sequence motifs. Taken together, this study provides a comprehensive characterisation of the gene regulatory landscape in rare subpopulations of human HSPCs. The accompanying datasets should serve as a valuable resource for understanding adult hematopoiesis and a framework for analysing aberrant regulatory networks in leukemic cells.
Publisher: American Society of Hematology
Date: 30-03-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22487424.V1
Abstract: Supplementary Figure from Temozolomide and Radiotherapy versus Radiotherapy Alone in Patients with Glioblastoma, i IDH /i -wildtype: i Post Hoc /i Analysis of the EORTC Randomized Phase III CATNON Trial
Publisher: Springer Science and Business Media LLC
Date: 10-10-2022
DOI: 10.1186/S12874-022-01728-0
Abstract: Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6 th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly erse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, which we describe, along with approaches used to overcome them. Several confirmed international collaborations are now in place, and the registry is providing valuable data for clinicians, researchers, industry and government, including through presentations of results at major national and international conferences. Challenges in establishing the LaRDR have been successfully overcome and the registry is now a valuable resource for lymphoma clinicians, researchers, health economists and others in Australia, New Zealand and globally.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2013
Publisher: Springer Science and Business Media LLC
Date: 20-12-2023
Publisher: MDPI AG
Date: 22-02-2021
DOI: 10.3390/JPM11020152
Abstract: Follicular lymphoma (FL) is the most common indolent B-cell lymphoma. Advanced stage disease is considered incurable and is characterized by a prolonged relapsing/remitting course. A significant minority have less favorable outcomes, particularly those with transformed or early progressive disease. Recent advances in our understanding of the unique genetic and immune biology of FL have led to increasingly potent and precise novel targeted agents, suggesting that a chemotherapy-future may one day be attainable. The current pipeline of new therapeutics is unprecedented. Particularly exciting is that many agents have non-overlapping modes of action, offering potential new combinatorial options and synergies. This review provides up-to-date clinical and mechanistic data on these new therapeutics. Ongoing dedicated attention to basic, translational and clinical research will provide further clarity as to when and how to best use these agents, to improve efficacy without eliciting unnecessary toxicity.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Maher Gandhi.