• 8th international conference on oncolytic virus therapeutics

      Guinn, Barbara-Ann; Braidwood, Lynne; Parker, Alan; Peng, Kah-Whye; Seymour, Leonard (Mary Ann Liebert, 2014-12)
      The 8th International Conference on Oncolytic Virus Therapeutics meeting was held from April 10-13, 2014, in Oxford, United Kingdom. It brought together experts in the field of oncolytics from Europe, Asia, Australasia, and the Americas and provided a unique opportunity to hear the latest research findings in oncolytic virotherapy. Presentations of recent work were delivered in an informal and intimate setting afforded by a small group of attendees and an exquisitely focused conference topic. Here we describe the oral presentations and enable the reader to share in the benefits of bringing together experts to share their findings.
    • An analogue peptide from the cancer testis antigen, PASD1, induces CD8+ T cell-responses against naturally processed peptide.

      Hardwick, Nicola R.; Buchan, Sarah; Ingram, Wendy; Khan, Ghazala; Vittes, Gisella; Rice, Jason; Pulford, Karen; Mufti, Ghulam J.; Stevenson, Freda; Guinn, Barbara-Ann; et al. (Cancer Research Institute, 2013)
      We have previously identified the novel Cancer/Testis antigen PASD1 by immunoscreening a testis library with pooled acute myeloid leukemia (AML) patient sera. To develop a cytotoxic T lymphocyte (CTL)-inducing vaccine, we have now investigated the carboxy-terminal region, known to contain serological determinants, for MHC class I (HLA-A⋆0201)-binding peptides. Algorithm-selected natural peptides failed to show detectable HLA-A⋆0201 binding in T2 assays. However, anchor-modified analogue peptides showed enhanced binding, with decreased off-rates. Analogue peptide-loaded antigen-presenting cells (APCs) induced IFN-γ production by T cells from normal donors and patients. In addition, peptide-specific T cells could be expanded from cancer patients by stimulation with the PASD1 analogue peptide Pa14. For clinical application, a DNA fusion gene vaccine encoding Pa14 was designed and tested in "humanized" mice. Splenocytes from vaccinated mice showed in vitro cytotoxicity against tumour cells, either exogenously loaded with the corresponding wild-type peptide (Pw8) or expressing endogenously processed PASD1 protein. We show for the first time that a DNA vaccine encoding an altered PASD1 epitope can induce CTLs to target the natural peptide expressed by human tumour cells.
    • Analogue peptides for the immunotherapy of human acute myeloid leukemia

      Hofmann, Susanne; Mead, Andrew; Malinovskis, Aleksandrs; Hardwick, Nicola R.; Guinn, Barbara-Ann; University of Bedfordshire (Springer, 2015-10-05)
      The use of peptide vaccines, enhanced by adjuvants, has shown some efficacy in clinical trials. However, responses are often short-lived and rarely induce notable memory responses. The reason is that self-antigens have already been presented to the immune system as the tumor develops, leading to tolerance or some degree of host tumor cell destruction. To try to break tolerance against self-antigens, one of the methods employed has been to modify peptides at the anchor residues to enhance their ability to bind major histocompatibility complex molecules, extending their exposure to the T-cell receptor. These modified or analogue peptides have been investigated as stimulators of the immune system in patients with different cancers with variable but sometimes notable success. In this review we describe the background and recent developments in the use of analogue peptides for the immunotherapy of acute myeloid leukemia describing knowledge useful for the application of analogue peptide treatments for other malignancies.
    • Anti-tumor immunity in a model of acute myeloid leukemia

      Cheuk, Adam T.C.; Wells, James W.; Chan, Lucas; Westwood, Nigel B.; Berger, Stuart A.; Yagita, Hideo; Okumura, Ko; Farzaneh, Farzin; Mufti, Ghulam J.; Guinn, Barbara-Ann; et al. (informa healthcare, 2009-03)
      Whole-cell vaccines allow the induction of anti-tumor immune responses without the need to define tumor antigens. We wished to directly compare, for the first time, the capacity of B7-1, B7-2 and 4-1BB ligand (4-1BBL) costimulatory molecules to convert murine and human acute myeloid leukemia (AML) cells into whole vaccines. 32Dc-kit is a murine myeloid cell line, which develops an AML-like disease over a protracted period, emulating human AML disease development. 32Dc-kit cells were modified to express elevated levels of B7-1, B7-2 or 4-1BBL, and each led to tumor rejection, although only mice injected with 32Dc-kit/B7-2 cells were able to reject subsequent parental tumor cell challenge. T-cell deficient nude mice were able to reject the 32Dc-kit variants, but they could not reject parental cell challenge; however, we found no evidence of cytotoxic T lymphocyte or natural killer (NK) activity ex vivo suggesting that tumor cell killing was mediated by an immune response that could not be recapitulated using purified NK or T cells as lone effectors. In human allogeneic mixed lymphocyte reactions (MLRs), we found no single costimulatory molecule was more effective, suggesting that the induction of a universal anti-tumor response will require a combination of costimulatory molecules.
    • Application of the pMHC array to characterise tumour antigen specific T cell populations in leukaemia patients at disease diagnosis

      Brooks, Suzanne E.; Bonney, Stephanie A.; Lee, Cindy; Publicover, Amy; Khan, Ghazala; Smits, Evelien L.J.; Sigurdardottir, Dagmar; Arno, Matthew; Li, Demin; Mills, Ken I.; et al. (Public Library of Science, 2015-10-22)
      Immunotherapy treatments for cancer are becoming increasingly successful, however to further improve our understanding of the T-cell recognition involved in effective responses and to encourage moves towards the development of personalised treatments for leukaemia immunotherapy, precise antigenic targets in individual patients have been identified. Cellular arrays using peptide-MHC (pMHC) tetramers allow the simultaneous detection of different antigen specific T-cell populations naturally circulating in patients and normal donors. We have developed the pMHC array to detect CD8+ T-cell populations in leukaemia patients that recognise epitopes within viral antigens (cytomegalovirus (CMV) and influenza (Flu)) and leukaemia antigens (including Per Arnt Sim domain 1 (PASD1), MelanA, Wilms’ Tumour (WT1) and tyrosinase). We show that the pMHC array is at least as sensitive as flow cytometry and has the potential to rapidly identify more than 40 specific T-cell populations in a small sample of T-cells (0.8–1.4 x 106). Fourteen of the twenty-six acute myeloid leukaemia (AML) patients analysed had T cells that recognised tumour antigen epitopes, and eight of these recognised PASD1 epitopes. Other tumour epitopes recognised were MelanA (n = 3), tyrosinase (n = 3) and WT1126-134 (n = 1). One of the seven acute lymphocytic leukaemia (ALL) patients analysed had T cells that recognised the MUC1950-958 epitope. In the future the pMHC array may be used provide point of care T-cell analyses, predict patient response to conventional therapy and direct personalised immunotherapy for patients.
    • CD66a (CEACAM1) is the only CD66 variant expressed on the surface of plasma cells in multiple myeloma: a refined target for radiotherapy trials?

      Lee, Cindy; Guinn, Barbara-Ann; Brooks, Suzanne E.; Richardson, Deborah; Orchard, Kim H. (Wiley, 2010-06)
    • Clinical evaluation of cellular immunotherapy in acute myeloid leukaemia.

      Smits, Evelien L.J.; Lee, Cindy; Hardwick, Nicola R.; Brooks, Suzanne E.; Van Tendeloo, Viggo F.I.; Orchard, Kim H.; Guinn, Barbara-Ann; University of Antwerp (SpringerLink, 2011-06)
      Immunotherapy is currently under active investigation as an adjuvant therapy to improve the overall survival of patients with acute myeloid leukaemia (AML) by eliminating residual leukaemic cells following standard therapy. The graft-versus-leukaemia effect observed following allogeneic haematopoietic stem cell transplantation has already demonstrated the significant role of immune cells in controlling AML, paving the way to further exploitation of this effect in optimized immunotherapy protocols. In this review, we discuss the current state of cellular immunotherapy as adjuvant therapy for AML, with a particular focus on new strategies and recently published results of preclinical and clinical studies. Therapeutic vaccines that are being tested in AML include whole tumour cells as an autologous source of multiple leukaemia-associated antigens (LAA) and autologous dendritic cells loaded with LAA as effective antigen-presenting cells. Furthermore, adoptive transfer of cytotoxic T cells or natural killer cells is under active investigation. Results from phase I and II trials are promising and support further investigation into the potential of cellular immunotherapeutic strategies to prevent or fight relapse in AML patients.
    • Expression of CD66 in non-Hodgkin lymphomas and multiple myeloma.

      Guinn, Barbara-Ann; Bosslet, Klaus; Lee, Cindy; Richardson, Deborah; Orchard, Kim H.; University of Bedfordshire (Wiley, 2011-12)
    • The future of publishing scientific data: is it time to accept the wider publication of null data?

      Guinn, Barbara-Ann; University of Bedfordshire (E Cronicon, 2014-12)
      One of the most self-limiting dogmas’ which scientists submit themselves to is the avoidance of publishing negative data. This reflected the fact that authors generally do not write up and submit null data. The avoidance of publishing negative data (by authors and journals) ensures we only show experiments that worked and represent a clear story of success. Experiments which the research community remains ignorant of and which thus be repeated wasting the limited money currently available for research from the government and charities, and time which could be spent more productively, moving the field forward more rapidly. But how should the science community publish negative data? This Editorial discusses some of the concerns regarding publishing null data and ways we can move the bioscience forward through it's publication.
    • High and low, but not intermediate, PRAME expression levels are poor prognostic markers in myelodysplastic syndrome at disease presentation

      Liberante, Fabio G.; Pellagatti, Andrea; Boncheva, Viktoriya Bogdanova; Bowen, David T.; Mills, Ken I.; Boultwood, Jacqueline; Guinn, Barbara-Ann; University of Bedfordshire; Leeds Teaching Hospitals NHS Trust; Queens University Belfast; et al. (Wiley, 2013-07)
    • Identification and validation of targets for cancer immunotherapy: from the bench-to-bedside

      Khan, Ghazala; Brooks, Suzanne E.; Denniss, Frances; Sigurdardottir, Dagmar; Guinn, Barbara-Ann; University of Bedfordshire; University of Southampton; King’s College London; University of Tübingen (InTech OpenAccess, 2013)
    • Immunotherapy of acute myeloid leukaemia: development of a whole cell vaccine.

      Cheuk, Adam T.C.; Guinn, Barbara-Ann; King's College London School of Medicine (bioscience.org, 2008)
      Acute myeloid leukaemia (AML) is a difficult to treat disease and strategies, such as immunotherapy, which have the potential to eliminate residual tumour cells at first remission are required to reduce the incidence of relapse with its high associated mortality rates. T cells play an important role in tumor immunity and two signals are traditionally thought to be required to activate naive T cells; signal one through the major histocompatibility:antigen:T-cell receptor complex and signal two through costimulation. Many tumor associated antigens have been identified in AML suggesting it may be possible to target the immune system of AML patients; however AML develops due to tumour and immune editing, two systems by which AML cells can escape immune surveillance. By genetically modifying AML cells to express costimulatory molecules and/or cytokines, it has been possible to transform AML cells into antigen presenting cells and this has the potential to re-activate the immune system in patients. Here we summarize the rationale for using a whole cell vaccine approach to treat AML, and discuss current progress in the field of whole cell vaccine development against AML.
    • Infrequent expression of the cancer-testis antigen, PASD1, in ovarian cancer

      Khan, Ghazala; Brooks, Suzanne E.; Mills, Ken I.; Guinn, Barbara-Ann; University of Bedfordshire; Southampton General Hospital; Queen’s University Belfast (Libertas Academica, 2015-08)
      Ovarian cancer is very treatable in the early stages of disease; however, it is usually detected in the later stages, at which time, treatment is no longer as effective. If discovered early (Stage I), there is a 90% chance of five-year survival. Therefore, it is imperative that early-stage biomarkers are identified to enhance the early detection of ovarian cancer. Cancer-testis antigens (CTAs), such as Per ARNT SIM (PAS) domain containing 1 (PASD1), are unique in that their expression is restricted to immunologically restricted sites, such as the testis and placenta, which do not express MHC class I, and cancer, making them ideally positioned to act as targets for immunotherapy as well as potential biomarkers for cancer detection where expressed. We examined the expression of PASD1a and b in a number of cell lines, as well as eight healthy ovary samples, eight normal adjacent ovarian tissues, and 191 ovarian cancer tissues, which were predominantly stage I (n = 164) and stage II (n = 14) disease. We found that despite the positive staining of skin cancer, only one stage Ic ovarian cancer patient tissue expressed PASD1a and b at detectable levels. This may reflect the predominantly stage I ovarian cancer samples examined. To examine the restriction of PASD1 expression, we examined endometrial tissue arrays and found no expression in 30 malignant tumor tissues, 23 cases of hyperplasia, or 16 normal endometrial tissues. Our study suggests that the search for a single cancer-testes antigen/biomarker that can detect early ovarian cancer must continue.
    • The innovative evolution of cancer gene and cellular therapies

      Lam, P.; Khan, Ghazala; Stripecke, R.; Hui, K.M.; Kasahara, N.; Peng, Kah-Whye; Guinn, Barbara-Ann (Nature Publishing Group, 2013-02-01)
      We provide an overview of the latest developments in cancer gene therapy--from the bench to early-stage clinical trials. We describe the most recent work of worldwide teams including experienced scientists and clinicians, reflecting the recent emergence of gene therapy from the 'Valley of Death'. The treatment efficacy of clinical gene therapy has now been shown in a number of diseases including cancer and we are observing a renewed interest by big pharmaceutical and biotechnology companies most obviously demonstrated by Amgen's acquisition of Biovex for up to USD$1 billion. There is an opportunity to be cautiously hopeful regarding the future of gene therapy in the clinic and we review here some of the most recent progress in the field.
    • International progress in cancer gene therapy

      Guinn, Barbara-Ann; Mulherkar, R.; King's College London (Nature Publishing Group, 2008-12)
      We overview the current status and most recent developments in the field of cancer gene therapy from an international viewpoint. We have largely based our review on presentations from the eighth annual meeting of the International Society for Cell and Gene Therapy of Cancer held in Mumbai, India (http://www.iscgt.com and http://www.iscgtindia.com). This has afforded us with the opportunity to describe the most recently published and unpublished data in the field of cancer gene therapy, gaining an insight into the priorities in this field today. In doing so, we hope to have provided a state of the art review of cancer gene therapy, with the help of some of the best-known researchers in the field. In addition, due to the location of the meeting, we had a unique opportunity to listen to some of the seminal cancer gene therapy work being performed in India at this time.
    • Is there a need to identify novel tumour antigens as targets for immunotherapy clinical trials for the removal of minimal residual disease in haematological malignancies?

      Guinn, Barbara-Ann; University of Bedfordshire (ACT Publishing Group, 2015-07)
      Despite the identification of many tumour antigens with the potential to act as targets for cancer vaccines and/or T-cell therapies very few have been used in clinical trials to date. This led to the timely development of a criteria which identified the ideal characteristics of tumour antigens which should be actively pursued for use in immunotherapy clinical trials. A list of 75 antigens were assessed against these criteria and although none harboured all of the characteristics identified as desirable, a number did show many of the characteristics identifying them as worthy of further pursuit to enable an organised development towards immunotherapy clinical trials. The study highlighted the benefit of focussing on a short list of antigens which would enable the rapid progress of a smaller number of antigens into clinical trials as targets for immunotherapy. However the antigens expressed by solid tumours often differ to those expressed by haematological malignancies, leading to this editorial which states the need for a similar study prioritising tumour antigens for use in clinical trials of haematological malignancies, independently of solid tumours. We also debate the importance of looking for new antigens in cancers in which few targets are known and discuss the importance of tumour antigens as biomarkers of disease diagnosis, stage and survival.
    • Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells.

      Greiner, Jochen; Bullinger, Lars; Guinn, Barbara-Ann; Döhner, Hartmut; Schmitt, Michael; University of Ulm (HighWire Press, 2008-11-15)
      Acute myeloid leukemia (AML) is the most common acute leukemia in adults. With intensive induction therapy, most patients younger than 60 years achieve complete remission. However, even if these younger patients were treated intensively, more than 50% will relapse. Clinical results of patients older than 60 years are more unfavorable. Therefore, in all patients with AML, the overall survival is still low. In the past decade, several leukemia-associated antigens (LAA) have been identified in patients with acute myeloid leukemia. BAGE, BCL-2, OFA-iLRP, FLT3-ITD, G250, hTERT, PRAME, proteinase 3, RHAMM, survivin, and WT-1 are all LAAs that have been shown to induce CD8+ T-cell recognition and for some antigens also humoral immune responses. Interestingly, most of these LAAs are linked to cell cycle or proliferation. This article discusses the balance between LAA-driven leukemia cell expansion and the elimination of these cells through attacks on LAAs by the immune system. Current knowledge of the function and CD8+ T-cell recognition of LAAs is reviewed and an outlook is given on how to improve T-cell responses to LAAs in acute myeloid leukemia cells.
    • The MEtabolomics to characterise Dietary Exposure (MEDE) Study: kinetics of metabolite responses to a test breakfast

      Favé, Gaëlle; Zhou, S.; Beckmann, M.E.; Harold, Graham; Lin, Wanchang; Tailliart, K.N.; Draper, J.H.; Mathers, John C.; Newcastle University; Aberystwyth University (Cambridge University Press, 2010)