Graham P Cook

University of Leeds, Leeds, England, United Kingdom

Are you Graham P Cook?

Claim your profile

Publications (36)191.57 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In summary, the low numbers of NK cells in PNH affect overall cytotoxicity, but this defect is not severe enough to manifest as heightened susceptibility to viral infection as seen in NKD.
    Blood 02/2015; 125(8):1351. DOI:10.1182/blood-2014-07-591255 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.
    Proceedings of the National Academy of Sciences 12/2014; 111(52). DOI:10.1073/pnas.1411072112 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human natural killer (NK) cells play an important role in antiviral immunity. However, studying their activation kinetics during infection is highly problematic. A clinical trial of a therapeutic virus provided an opportunity to study human NK cell activation in vivo in a controlled manner. Ten colorectal cancer patients with liver metastases received between one and five doses of oncolytic reovirus prior to surgical resection of their tumour. NK cell surface expression of the interferon-inducible molecules CD69 and tetherin peaked twenty-four to forty-eight hours post-infection, coincident with a peak of interferon-induced gene expression. The interferon response and NK cell activation were transient, declining by ninety-six hours post-infection. Furthermore, neither NK cell activation nor the interferon response were sustained in patients undergoing multiple rounds of virus treatment. These results show that reovirus modulates human NK cell activity in vivo and suggest that this may contribute to any therapeutic effect of this oncolytic virus. Detection of a single, transient peak of activation, despite multiple treatment rounds, has implications for the design of reovirus-based therapy. Furthermore, our results suggest the existence of a post-infection refractory period when the interferon response and NK cell activation are blunted. This refractory period has previously been observed in animal models and may underlie the enhanced susceptibility to secondary infections that is seen following viral infection. This article is protected by copyright. All rights reserved.
    Clinical & Experimental Immunology 12/2014; 180(1). DOI:10.1111/cei.12562 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Deregulated expression of the transmembrane glycoprotein CDCP1 (CUB domain-containing protein-1) has been detected in several cancers including colon, lung, gastric, breast, and pancreatic carcinomas. CDCP1 has been proposed to either positively or negatively regulate tumour metastasis. In this study we assessed the role of CDCP1 in properties of cells that are directly relevant to metastasis, namely adhesion and motility. In addition, association between CDCP1 and the tetraspanin protein CD9 was investigated. CDCP1 and CD9 protein expression was measured in a series of colon cancer cell lines by flow cytometry and Western blotting. Adhesion of Colo320 and SW480 cells was determined using a Matrigel adhesion assay. The chemotactic motility of SW480 cells in which CDCP1 expression had been reduced by RNA interference was analysed using the xCELLigence system Real-Time Cell Analyzer Dual Plates combined with 8 μm pore filters. Detergent-resistant membrane fractions were generated following density gradient centrifugation and the CDCP1 and CD9 protein composition of these fractions was determined by Western blotting. The potential association of the CDCP1 and CD9 proteins was assessed by co-immunoprecipitation. Engineered CDCP1 expression in Colo320 cells resulted in a reduction in cell adhesion to Matrigel. Treatment of SW480 cells with CDCP1 siRNA reduced serum-induced chemotaxis. CDCP1 and CD9 cell-surface protein and mRNA levels showed a positive correlation in colon cancer cell lines and the proteins formed a low-level, but detectable complex as judged by co-sedimentation of detergent lysates of HT-29 cells in sucrose gradients as well as by co-immunoprecipitation in SW480 cell lysates. A number of recent studies have assigned a potentially important role for the cell-surface protein CDCP1 in invasion and metastasis of a several types of human cancer cells. In this study, CDCP1 was shown to modulate cell-substratum adhesion and motility in colon cancer cell lines, with some variation depending on the colon cancer cell type. CDCP1 and CD9 were co-expressed at the mRNA and protein level and we obtained evidence for the presence of a molecular complex of these proteins in SW480 colon cancer cells.
    BMC Cancer 10/2014; 14(1):754. DOI:10.1186/1471-2407-14-754 · 3.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rheumatoid arthritis (RA) is a polygenic disorder usually arising from combined genetic predisposition and environmental influences with associated dysfunctional immune responses. The X-box binding protein 1 (XBP1) transcription factor is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes including RA. XBP1 can also be activated in direct response to Toll-like Receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Our aim was to investigate the relevance of interactions between UPR and TLR signalling pathways in the serum and synovial fibroblasts (SFs) of patients with RA, using samples from healthy individuals and patients with osteoarthritis (OA) as controls Peripheral blood mononuclear cells (PBMC) were obtained from control groups: healthy individuals (n = 24) and RA patients, comprising active disease (n = 47) and remission (n = 12). SFs from RA and OA patients were isolated by digestion of synovial biopsies. Gene expression profiling was performed using qPCR for the detection of sXBP1 and enzyme-linked immunosorbent assays (ELISA) to quantify levels of pro-inflammatory cytokines, IL-6 and TNF. siRNA targeting of XBP1 was used for knockdown experiments in SFs. We investigated the expression of ER stress response genes in patients with active RA and patients in remission. We show that TLR-dependent XBP1 activation is operative in the SFs of patients with active RA. The active (spliced) form of (s)XBP1 was significantly overexpressed in the active RA group compared to healthy controls and patients in remission (p = 0.01). Paradoxically, expression of nine other ER stress response genes was reduced in active RA compared to patients in remission, suggestive of a UPR-independent process. However, sXBP1 was induced in SFs by TLR4 and TLR2 stimulation, resulting in sXBP1-dependent IL-6 and TNF production. We also show that TNF itself induces sXBP1 in SFs, thus generating a potential feedback loop for sustained activation of these cells. sXBP1 plays a central role in two different cellular processes that may first appear unconnected. However, linking inflammatory pathways with ER stress provides SFs with a timely, coordinated and protective response. XBP1 activation may therefore be a suitable target in the treatment of RA, since it forms a cornerstone of two different molecular processes implicated in the pathogenesis of RA.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A22. DOI:10.1136/annrheumdis-2013-205124.51 · 10.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The assembly of a molecular scaffold termed the NLRP3-inflammasome complex, in monocytes, macrophages and dendritic cells, leads to the cleavage of pro-interleukin-1β(pro-IL-1β) into active IL-1β, a proinflammatory cytokine involved in innate immune responses (1). Overactivity of the NLRP3 inflammasome, leading to excessive IL-1βrelease, is involved in several autoinflammatory diseases, from cryopyrin-associated periodic syndromes (CAPS) to gouty arthritis (2). Objectives To characterize the expression of the NLRP3-inflammasome components at the transcriptional level, in peripheral blood mononuclear cells (PBMCs) of patients with active RA undergoing treatment with infliximab (IFX). Methods All RA patients included (n=31) were diagnosed according to the 1987 ACR criteriaand selected for IFX therapy because of a high disease activity (DAS28 ≥5.1), despite conventional DMARD treatment. Peripheral blood was obtained at the time of starting IFX (baseline), and again at week 14 of treatment. The DAS28 response at week 14 was recorded according to EULAR criteria, and also as the relative change from baseline. Blood samples were also obtained from 22 age- and sex-matched healthy controls (HCs). Total RNA was extracted from PBMCs and prepared for qRT-PCR: the relative expression of ASC, pyrin, NLRP3 FL (full-length isoform) and SL (short-length) and caspase-1 transcripts were assessed. Statistical analyses were performed using non-parametric Wilcoxon and Mann-Whitney tests, for paired and unpaired samples respectively. Results At baseline, the transcriptional levels of ASC, pyrin, NLRP3 FL, NLRP3 SL, and caspase-1 were higher in PBMCs of RA patients than in HCs (p=0.0324, 0.0244, 0.0028, 0.0002 and 0.0168 respectively). By comparing transcript levels between baseline and week 14, we identified two groups of patients, one with upregulation of ASC (n=14) and the other with downregulation of ASC (n=10); the relative improvement in DAS28 was significantly higher in the latter group (p=0.0092). No correlations were found between response to IFX and changes in levels of the other transcripts. Conclusions NLRP3-inflammasome-related transcripts in PBMCs were upregulated in active RA prior to receiving biologics therapy. Clinical response in patients undergoing IFX therapy may be partially explained by downregulation of ASC, for which a role independent of the NLRP3-inflammasome has recently been reported (3). Disclosure of Interest None Declared
    Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):i-641. DOI:10.1136/annrheumdis-2012-eular.66 · 10.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the RAS family of oncogenes are highly prevalent in human cancer and, amongst its manifold effects, oncogenic RAS impairs the expression of components of the antigen presentation pathway. This allows evasion of cytotoxic T lymphocytes (CTL). CTL and natural killer (NK) cells are reciprocally regulated by MHC class I molecules and any gain in CTL recognition obtained by therapeutic inactivation of oncogenic RAS may be offset by reduced NK cell activation. We have investigated the consequences of targeted inactivation of oncogenic RAS on the recognition by both CTL and NK cells. Inactivation of oncogenic RAS, either by genetic deletion or inactivation with an inducible intracellular domain antibody (iDAb), increased MHC class I expression in human colorectal cell lines. The common RAS mutations, at codons 12, 13 and 61, all inhibited antigen presentation. Although MHC class I modulates the activity of both CTL and NK cells, the enhanced MHC class I expression resulting from inactivation of mutant KRAS did not significantly affect the in vitro recognition of these cell lines by either class of cytotoxic lymphocyte. These results show that oncogenic RAS and its downstream signalling pathways modulate the antigen presentation pathway and that this inhibition is reversible. However, the magnitude of these effects was not sufficient to alter the in vitro recognition of tumour cell lines by either CTL or NK cells.
    Molecular Immunology 12/2013; 58(2):160-168. DOI:10.1016/j.molimm.2013.11.020 · 3.00 Impact Factor
  • Source
    Dataset: Document1
  • Source
    Dataset: Document1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In paroxysmal nocturnal hemoglobinuria (PNH), hematopoietic cells lacking glycosylphosphatidylinositol (GPI)-linked proteins on their surface (GPI(neg)) exist alongside normal (GPI+) cells. Analysis of NK cell subsets in forty-seven PNH patients revealed that the ratio of CD56(bright):CD56(dim) NK cells differed in the GPI+ and GPI(neg) populations, with GPI(neg)CD56(bright) NK cells significantly more abundant in peripheral blood than their normal GPI+ counterparts. Indeed, GPI+CD56(bright) NK cells were not detected in the peripheral blood of some patients, suggesting their trafficking to a niche unavailable to the GPI(neg)CD56(bright) NK cell population. Defective cellular trafficking in this disease was supported by findings showing differential chemokine receptor expression between GPI+ and GPI(neg) NK cells and impaired SDF-1 induced chemotaxis of GPI(neg) NK cells. Our results indicate a role for GPI-linked proteins in NK cell subset homeostasis and suggest that differential chemokine responses might contribute to the balance of GPI+ and GPI(neg) populations in this disease.
    Blood 07/2013; 122(11). DOI:10.1182/blood-2013-06-507574 · 10.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
    Annals of the rheumatic diseases 05/2013; 73(6). DOI:10.1136/annrheumdis-2013-203276 · 10.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reovirus is a promising oncolytic virus, acting by both direct and immune-mediated mechanisms, although its potential may be limited by inactivation following systemic delivery. This study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus-loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Whilst direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus following intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer cells within reovirus-treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a type I interferon-dependent manner. Similarly, natural killer cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells and this blood cell carriage has the potential to instigate both direct and innate immune-mediated therapy against human colorectal or other cancers metastatic to the liver. © 2012 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2013; 132(10). DOI:10.1002/ijc.27918 · 5.01 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The rodent papillomaviruses (PVs) have great potential to be utilized as a model for PV infection and oncogenesis since mice and rats have well-studied genetics and similar physiology to humans, as well as the ready availability of many reagents for the study of host cell biology and immunology. Rodent PVs have been isolated and their genomes have been sequenced, however the role of the rodent PV oncoproteins in cell transformation is still relatively unknown. We have cloned and expressed the E6 and E7 open reading frames (ORFs) of Micromys minutus papillomavirus 1 (MmiPV1), introducing epitope tags to enable the identification of expressed proteins. Initial results showed that both E6 and E7 were located in the nucleus and the cytoplasm of transiently-transfected established mouse BALB/c 3T3 cells and A549 cells. In contrast, E6 and E7 of HPV16 were localized predominantly in the nucleus. Preliminary observations on the transforming ability of individual MmiPV1 E6 and E7 ORFs suggested that neither protein was able to morphologically or functionally transform established BALB/c 3T3 or primary baby rat kidney (BRK) cells. Current investigations are focused on possible cooperation of both proteins and the involvement of cellular oncogenes (e.g. activated ras) in transformation of established and primary cells.
    Faculty of Biological Sciences Postgraduate Symposium 2013; 04/2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: X-box binding protein 1 (XBP1) is a central regulator of the endoplasmic reticulum (ER) stress response. It is induced via activation of the IRE1 stress sensor as part of the unfolded protein response (UPR) and has been implicated in several diseases processes. XBP1 can also be activated in direct response to Toll-like receptor (TLR) ligation independently of the UPR but the pathogenic significance of this mode of XBP1 activation is not well understood. Here we show that TLR-dependent XBP1 activation is operative in the synovial fibroblasts (SF) of patients with active rheumatoid arthritis (RA). We investigated the expression of ER stress response genes in patients with active RA and also in patients in remission. The active (spliced) form of (s)XBP1 was significantly overexpressed in the active RA group compared to healthy controls and patients in remission. Paradoxically, expression of nine other ER stress response genes was reduced in active RA compared to patients in remission, suggestive of a UPR-independent process. However, sXBP1 was induced in SF by TLR4 and TLR2 stimulation, resulting in sXBP1-dependent interleukin-6 and tumour necrosis factor (TNF) production. We also show that TNF itself induces sXBP1 in SF, thus generating a potential feedback loop for sustained SF activation. These data confirm the first link between TLR-dependent XBP1 activation and human inflammatory disease. sXBP1 appears to play a central role in this process by providing a convergence point for two different stimuli to maintain activation of SF.
    Journal of Autoimmunity 01/2013; 50(100). DOI:10.1016/j.jaut.2013.11.002 · 7.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune evasion is now recognized as a key feature of cancer progression. In animal models, the activity of cytotoxic lymphocytes is suppressed in the tumour microenvironment by the immunosuppressive cytokine, Transforming Growth Factor (TGF)-β. Release from TGF-β-mediated inhibition restores anti-tumour immunity, suggesting a therapeutic strategy for human cancer. We demonstrate that human natural killer (NK) cells are inhibited in a TGF-β dependent manner following chronic contact-dependent interactions with tumour cells in vitro. In vivo, NK cell inhibition was localised to the human tumour microenvironment and primary ovarian tumours conferred TGF-β dependent inhibition upon autologous NK cells ex vivo. TGF-β antagonized the interleukin (IL)-15 induced proliferation and gene expression associated with NK cell activation, inhibiting the expression of both NK cell activation receptor molecules and components of the cytotoxic apparatus. Interleukin-15 also promotes NK cell survival and IL-15 excluded the pro-apoptotic transcription factor FOXO3 from the nucleus. However, this IL-15 mediated pathway was unaffected by TGF-β treatment, allowing NK cell survival. This suggested that NK cells in the tumour microenvironment might have their activity restored by TGF-β blockade and both anti-TGF-β antibodies and a small molecule inhibitor of TGF-β signalling restored the effector function of NK cells inhibited by autologous tumour cells. Thus, TGF-β blunts NK cell activation within the human tumour microenvironment but this evasion mechanism can be therapeutically targeted, boosting anti-tumour immunity.
    PLoS ONE 09/2011; 6(9):e22842. DOI:10.1371/journal.pone.0022842 · 3.23 Impact Factor
  • 51st Annual Scientific Meeting of the British-Society-for-Haematology; 04/2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NK cell activation is negatively regulated by the expression of target cell MHC class I molecules. We show that this relationship is nonlinear due to an NK cell activation/inhibition threshold. Ewing's sarcoma family tumor cell monolayers, which were highly susceptible to NK cells in vitro, developed a highly resistant phenotype when cultured as three-dimensional multicellular tumor spheroid structures. This suggested that tumor architecture is likely to influence the susceptibility to NK cells in vivo. Resistance of the multicellular tumor spheroid was associated with the increased expression of MHC class I molecules and greatly reduced NK cell activation, implying that a threshold of NK cell activation/inhibition had been crossed. Reducing MHC class I expression on Ewing's sarcoma family tumor monolayers did not alter their susceptibility to NK cells, whereas increased expression of MHC class I rendered them resistant and allowed the threshold point to be identified. This threshold, as defined by MHC class I expression, was predictive of the number of NK-resistant target cells within a population. A threshold permits modest changes in the target cell surface phenotype to profoundly alter the susceptibility to NK cells. Whereas this allows for the efficient detection of target cells, it also provides a route for pathogens and tumors to evade NK cell attack.
    The Journal of Immunology 02/2011; 186(3):1538-45. DOI:10.4049/jimmunol.1000951 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cytotoxic lymphocytes eliminate infected cells and tumours via the perforin-mediated delivery of pro-apoptotic serine proteases known as granzymes. Granzyme B triggers apoptosis via the cleavage of a repertoire of cellular proteins, leading to caspase activation and mitochondrial depolarization. A simple bioinformatics strategy identified a candidate granzyme B cleavage site in the widely expressed BNIP-2 (BCL2/adenovirus E1B-19K protein-interacting protein 2). Granzyme B cleaved recombinant BNIP-2 in vitro and endogenous BNIP-2 was cleaved during the NK (natural killer) cell-mediated killing of tumour cells. Cleavage required the site identified in the bioinformatics screen and was caspase-independent. Expression of either full-length BNIP-2 or a truncated molecule mimicking the granzyme B cleaved form was pro-apoptotic and led to the caspase-dependent cleavage of BNIP-2 at a site distinct from granzyme B cleavage. Inhibition of BNIP-2 expression did not affect the susceptibility to NK cell-mediated killing. Furthermore, target cells in which BID (BH3-interacting domain death agonist) expression was inhibited also remained highly susceptible to NK cell-mediated killing, revealing redundancy in the pro-apoptotic response to human cytotoxic lymphocytes. Such redundancy reduces the opportunity for escape from apoptosis induction and maximizes the chances of immune-mediated clearance of infected cells or tumour cells.
    Biochemical Journal 11/2010; 431(3):423-31. DOI:10.1042/BJ20091073 · 4.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This phase I study in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of s.c. treatment of human recombinant interleukin 21 (IL-21). Phase I dose-escalation trial with treatment of three to six patients at each dose level, escalating from 3 to 300 μg/kg. Treatment was administered s.c. on an outpatient basis 3 days per week for 8 or 16 weeks. Twenty-six patients entered the study. Recombinant IL-21 was generally well tolerated, and dose-limiting toxicities (DLT) were first seen at dose levels of 200 and 300 μg/kg. The following four DLTs were observed in three patients: increased transaminases, increased hyperbilirubinemia, hypersensitivity reaction, and lethargy. The MTD was declared to be 200 μg/kg, although five of seven patients at the 300 μg/kg dose level experienced no DLTs. A treatment-related effect on soluble CD25 was observed at all dose levels and increased with dose level. Furthermore, higher doses induced interferon-γ, perforin, and granzyme B mRNA expression in peripheral blood, and granzyme B protein expression in both CD8(+) T cells and natural killer cells, consistent with the activation of cytotoxic lymphocytes. Three patients, one patient with MM and two with RCC, obtained a partial response. Outpatient treatment with s.c. administered IL-21 was tolerated and had dose-dependent pharmacodynamics. rIL-21 showed antitumor activity in patients with MM and RCC.
    Clinical Cancer Research 10/2010; 16(21):5312-9. DOI:10.1158/1078-0432.CCR-10-1809 · 8.19 Impact Factor
  • D.J. Orchard-Webb · G.P. Cook · G.E. Blair
    EJC Supplements 06/2010; 8(5):123. DOI:10.1016/S1359-6349(10)71283-0 · 9.39 Impact Factor

Publication Stats

551 Citations
191.57 Total Impact Points

Institutions

  • 2005–2015
    • University of Leeds
      • Leeds Institute of Molecular Medicine (LIMM)
      Leeds, England, United Kingdom
  • 2013
    • Leeds Teaching Hospitals NHS Trust
      Leeds, England, United Kingdom
  • 2008–2010
    • St. James University
      Сент-Джеймс, New York, United States
  • 2007–2010
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom