Identification, characterisation and therapeutic targeting of leukaemic stem/propagating cells in Acute Myeloid Leukaemia

Lead Research Organisation: University of Oxford

Abstract

There are ~3000 new cases a year in the UK of Acute Myeloid Leukaemia (AML). This is the most common aggressive leukaemia. Despite advances in treating patients under the age of 60 years, 50% of these patients still die of their disease. Furthermore, 80% of patients are over the age of 60 and in this age group only 5% of patients are cured. Thus, we need to improve therapy.

AML mainly arises sporadically through acquisition of genetic changes in DNA in multiple genes that regulate the complex process of blood cell production. In some patients there is a preleukaemia condition called Myelodysplasia (MDS). One way to further our understanding AML is to define the compendium of genetic changes throughout all our DNA in both AML and MDS and assess how changes deregulate normal blood stem and progenitor cells and transform them into cancerous populations. This necessary information provides a rational platform for future developments to directly benefit patient care. Furthermore study of MDS and AML provides a model to discover general principles in cancer biology and therapy.

Technical Summary

Our aim is to characterise the heterogeneous populations of leukaemia propagating cells (LPC) in adult and childhood Acute Myeloid Leukaemia (AML) at functional, genetic, epigenetic and molecular levels, eventually at a single cell level, to improve our basic understanding of leukaemia initiation and propagation. The ultimate aim is to translate this knowledge to improve survival rates in patients.
Recent studies from our laboratory and other laboratories have shown that, within any one patient’s tumour, there is functional, molecular and genetic heterogeneity of tumour propagating populations. Though not yet formally demonstrated, layered upon this will likely be epigenetic heterogeneity.
Thus, our key questions centre around understanding: a) the nature of this heterogeneity; b) how it arises and c) how different aspects of heterogeneity impact on each other.
From a tumour biology perspective, a central hypothesis we will work towards testing is that there are specific molecular attributes present in AML LPC, but absent in downstream progeny, that explain LPC’s ability to propagate tumours whereas downstream progeny cannot.
Experimentally, these studies will initially be cell population based. We will purify distinct immunophenotypic primary human AML populations, test their in vivo function, and determine their molecular, genetic and epigenetic profiles. This will be an iterative process. But, ultimately, these studies will have to be conducted at the single cell level,. To begin with, we will overlay single cell molecular and genetic analysis on the cell population-based studies.
From a translational standpoint, our key hypotheses are: A) AML LPC are the chemoresistant relapse-driving populations. B) LPC can be therapeutically targeted. Only if both hypotheses are proven correct will be able to improve survival for patients.
To test the first hypothesis, we will track LPC from diagnosis through therapy. To address the second hypothesis, we will continue work with Stanford to develop a combination of therapeutic antibodies targeting LPC antigens. Once again, there are huge challenges here, that include: a) defining a window between efficacy and toxicity given that many LPC markers are widely expressed b) defining cocktails of antibodies that target all chemoresistant LPCs.

Publications

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Andreeff M (2016) Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Craddock C (2016) Tolerability and Clinical Activity of Post-Transplantation Azacitidine in Patients Allografted for Acute Myeloid Leukemia Treated on the RICAZA Trial. in Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

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Craddock CF (2017) Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature. in Clinical cancer research : an official journal of the American Association for Cancer Research

 
Description Geoff Thomas Foundation
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Prof Vyas has advised the Geoff Thomas Foundation (GTF) (http://www.geoffthomasfoundation.org/site/index.php) - a Football Association (FA) charity raising money and awareness to fight blood cancers. Dr Vyas has attended meetings with parliamentarians, research funders (CRUK, LR and DoH) with Geoff Thomas Foundation. There was a successful application to the Leukaemia and Lymphoma Research Clinical Trials Advisory Panel (http://www.lrf.org.uk/en/1/scirespan.html), with support from GTF to raise funding for national clinical trials group for early phase trials in blood cancers.
URL http://www.geoffthomasfoundation.org/site/index.php
 
Description IMPACT - Transplantation Trials Practice
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description LSC detection is now part of the UK AML trial laboratory studies fro MRD detection
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact The change if validated over the next 2-3 years will transform the detection of residual leukaemia post therapy and have implication for the necessity of additional post remission therapy. There will be implications for other cancers as a whole.
 
Description Monitoring of Acute Myeloid Leukaemia stem cells (LSC) in patients receiving treatment
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Our protocol of monitoring AML LSC has changed national practice. This is now routine for UK AML trials that recruit 95% of all UK AML patients under 60 years old.
 
Description NHSBT Non-Executive Director
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Ensuring quality and safe provision of blood and organs.
 
Description UK Clinical Guidelines on the Treatment of Myelodysplasia
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description UK Stem Cell Strategic Forum
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Provided evidence on how to structure research and development using blood stem cells for a Report commissioned by DoH and involving NHSBT, Anthony Nolan Trust, DoH, Lead clinicians in Bone Marrow transplantation and members of the Devolved Administrations.
 
Description 2009 Disease Team Award
Amount £2,200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2010 
End 05/2014
 
Description CRUK Programme Grant
Amount £440,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2012 
End 06/2017
 
Description Celgene Corp (USA) Celgene funded post-doctoral fellowship programme
Amount £423,141 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 08/2015 
End 07/2017
 
Description Celgene PhD Studentship
Amount £174,000 (GBP)
Organisation Celgene 
Sector Private
Country United States
Start 09/2010 
End 08/2013
 
Description HIDI Award
Amount £25,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2018 
End 07/2019
 
Description Haematology and Stem Cell Theme Oxford Biomedical Research Centre (NIHR)
Amount £125,000,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description LLR Project Grant
Amount £195,016 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2012 
End 09/2014
 
Description LLR, Programme Grant
Amount £1,369,070 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2013 
End 11/2018
 
Description Leukaemia Lymphoma Research Programme Grant
Amount £1,378,340 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 07/2018
 
Description MRC Molecular Haematology Unit Award
Amount £520,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 03/2017
 
Description Medical Research Council (MRC) - Molecular Haematology Unit Award
Amount £1,387,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 04/2022
 
Description Oxford BRC - Joint Application
Amount £780,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2017
 
Description PADI2 inhibitior as a therapy targeting acute myeloid leukemia initiating cells
Amount £175,487 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2017
 
Description Understanding heterogeneity of treatment response in 'standard' risk acute myeloid leukaemia
Amount £275,279 (GBP)
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2018
 
Description WT CLinical Training Fellowship
Amount £218,356 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 05/2016
 
Description Wellcome Trust, ISSF - Institutional Strategic Support Fund
Amount £49,234 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2015 
End 06/2017
 
Title Bone marrow cells 
Description Collection of 3000 frozen viable cells patients with AML and Myelodysplasia (MDS) a preleukaemic form of AML. 
Type Of Material Biological samples 
Year Produced 2009 
Provided To Others? Yes  
Impact 2 papers in NEJM and 3 paper in BLood 2 in Leukaemia 
 
Title Clinical and biological database of myeloid diseases 
Description We have developed secure web-based databases of clinical data associated with 439 bone marrow samples taken from patients with diseases affecting myeloid blood cells (Leukaemia and pre-leukaemia disorders). Clinical details are now automatically entered from collaborating NHS Trusts under approved protocols. The clinical data is linked to secure web-based databases containing detailed molecular, cellular and functional characterisation of stem and progenitor blood compartments from patient samples. 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact This has allowed us to publish papers (PubMed IDs below) and secure the MRC Disease Team Award. PubMed IDs 19664981 19546437 19644143 
URL http://europepmc.org/abstract/MED/19664981
 
Title Fluorescence activated cell sort based protocol to monitor Acute Myeloid Leukaemia stem cells (LSCs). 
Description We have developed technology to monitor AML LSCs in all patients treated in UK AML NCRN (National Cancer Regional Network) Trials at diagnosis and following treatment. 
Type Of Material Biological samples 
Year Produced 2008 
Provided To Others? Yes  
Impact This technology has been transferred to the NHS. For the first time, this study will determine if eradication cancer stem cells is required to cure cancer. 
 
Title Improving single cell biology 
Description Jointly with the WIMM single cell facility we are developing novel methods to analyse the total complement of a cell's nucleic acid and anlsyse chromatin structure. 
Type Of Material Technology assay or reagent 
Year Produced 2016 
Provided To Others? Yes  
Impact Multiple research projects have been developed from these tools. 
 
Title New antibodies to detect AML LSC 
Description New antibodies to detect AML LSC 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Evaluation of the use of this research material is still in progress 
 
Description Biology of leukaemia stem cells in CML blast crisis. 
Organisation University of Glasgow
Department College of Medical, Veterinary and Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Fuctional and clonal evaluation of LSC's
Collaborator Contribution FISH analysis
Impact Publication - Kinstrie R*, Karamitros D* Goardon N, Morrison H, Hamblin M, Robinson L, Clark RE, Copland M*, and Vyas P*. Heterogeneous Leukemia Stem Cells In Myeloid Blast Phase Chronic Myeloid Leukemia. Blood Advances (2016 in press).
Start Year 2014
 
Description Childhood AML 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Isolation and purification of leukaemic stem cells in childhood AML.
Collaborator Contribution Intellectual contribution. Contribution to some experiments.
Impact Initiation of the first UK childhood AML clinical trial - Mye01. Vyas lab will be performing leukemic stem cell minimal residual disease flow cytometry analysis on sequential samples from this trial for risk stratification purposes.
Start Year 2012
 
Description Clinical Trial of Anti-CD47 
Organisation Leeds Teaching Hospitals NHS Trust
Department Department of Clinical Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation Royal Liverpool University Hospital
Department Department of Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation Stanford University
Department Stem Cell Institute Stanford
Country United States 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation The Christie NHS Foundation Trust
Department Haematology and Transplant Unit
Country United Kingdom 
Sector Hospitals 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University Hospital of Wales
Department Department of Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University of Nottingham
Department Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Clinical Trial of Anti-CD47 
Organisation University of Oxford
Department Department of Oncology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have written the Phase I clinical trial Protocol for use of Anti-CD47 in a first in class first in man clinical trial. I will coordinate CTA application and NRES application. My lab will perform exploratory PD biomarker analysis. I will be CI of the trial. Phase I trial to started 2015. Phase II trials to start 2017.
Collaborator Contribution Stanford University have made the therapeutic. There are 5 UK hospitals site that will run the trial. A company, CD47 Inc, has spun out of Stanford University and is now the sponsor of this trial. Oxford University has a revenue sharing agreement with Stanford University.
Impact 1. We successfully secured MRC (2015 and 2009 ) and Bloodwise (2015) funding for this trial. 2. The drug is safe we will aim to perform a Phase II trial in 2017 in AML.
Start Year 2010
 
Description Collaboration on therapy of high risk MDS and AML. 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Understanding AML Leukaemic stem cell biology. Assessment of Leukaemic stem cells (LSC) as a marker of minimal residual disease. This is evaluated using samples from clinical trials.
Collaborator Contribution Clinical Trial Lead
Impact Quek L*, Ferguson P*, Metzner M, Ahmed I, Kennedy A, Garnett C, Jeffries S, Walter C, Piechocki K, Timbs A, Danby R, Raghavan M, Peniket A, Griffiths M, Bacon A, Ward J, Wheatley K, Vyas P*, Craddock C*. Mutational Analysis of Disease Relapse in Patients Allografted for Acute Myeloid Leukemia Khan N, Hills RK, Knapper S, Steadman L, Qureshi U, Rector JL, Bradbury C, Russell NH, Vyas P, Burnett AK, Grimwade D, Hole PS, Freeman SD. Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia PLoS One. 2016 Sep 26;11(9):e0163291. PMID: 27669008 Craddock C, Jilani NY, Siddique S, Yap C, Khan JN, Nagra S, Ward J, Ferguson P, Hazlewood P, Buka R, Vyas P, Goodyear OC, Tholouli E, Crawley C, Russell N, Byrne J, Malladi R, Snowden JA, Dennis M. Tolerability and clinical activity of post-transplant Azacitidine in patients allografted for Acute Myeloid Leukaemia treated on the RICAZA trial. Biol Blood Marrow Transplant. Sep 9. pii: S1083-8791(15)00609-6. doi: 10.1016/j.bbmt.2015.09.004. (2015). Bradbury C, Houlton AE, Akiki S, Gregg R, Rindl M, Khan J, Ward J, Khan N, Griffiths M, Nagra S, Hills R, Burnett A, Russell N, Vyas P, Grimwade D, Craddock C, Freeman SD. Prognostic value of monitoring a candidate immunophenotypic leukemic stem/progenitor cell population in patients allografted for acute myeloid leukemia. Leukemia. 29 p988-91. (2014) PMID:25425198. Craddock C, Goardon N, Quek L, Freeman S, Siddique S, Raghavan M, Schuh A, Grimwade D, Virgo P, Hills R, McSkeane T, Arrazi J, Gilkes A, Knapper, Adam Ivey, Brookes C, Miles O, Davies B, Chaudhury S, Pollard T, Price A, Atzberger A, Wall K, Kaur H, Griffiths M, Cavenagh, Majeti R, Weissman I, Burnett A, Vyas P. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukaemia 27:p1028-36 (2013). Goodyear O, Dennis M, Loke J, Jilani N, Siddique S, Ryan G, J Nunnick, Khanum R, Raghavan M, Cook M, Snowden J, Griffiths M, Russell N, Yin J, Crawley C, Cook G, Vyas P, Moss P, Malladi R, Craddock C. Azacitidine Induces Expansion of Regulatory T Cells and Induces a Tumor Antigen Specific Response after Allogeneic Stem Cell Transplantation in patients with AML. Blood. 119: p3361-9. (2012). Co-administration of Vorinostat Does Not Improve Outcome of Patients with of Acute Myeloid Leukemia Treated with Azacitidine Charles Craddock, MD, PhD1, Aimee E Houlton, BSc, MSc2*, Lynn Swun Quek, DPhil, FRCPath, Paul Ferguson, MBChB MRCP PhD3; Emma Gbandi, Corran Roberts (affiliation and degree needed), *, Marlen Metzner, Alison Kennedy, Manoj Raghavan4*, Sandeep Nagra1*, Louise Dudley, BSc, MRes5*, DPhil, MBBS6*, Sharon Love, Jamie D. Cavenagh7, Michael Dennis, FRCPath8*, Mary Frances McMullin, MD9, Srinivas P Pillai10*, Richard Kelly, BSc, MD11*, Shamyla Siddique12*, Keith Wheatley, DPhil13 and Paresh Vyas, BM, DPhil, FRCP, FRCPath14 Submitted Grants: 2015-2018 Therapy Acceleration Programme £92 778. Leukaemia Lymphoma Research Funded Trial Infrastructure Programme
Start Year 2012
 
Description Collaboration with the company Becton Dickinson 
Organisation Becton, Dickinson and Company
Country United States 
Sector Private 
PI Contribution We identified novel LSC surface antigens. We designed the panel. Both of these were done in collaboration with our colleagues in Stanford. We have tested the panel. We are obtaining data on patients undergoing treatment in the UK AML trials.
Collaborator Contribution The company has developed a new series of monoclonal antibody reagents for FACS-based detection of leukaemic stem cells (LSC) based on our data and data in the field. We are evaluating the commercial possibility of using a FACS-based LSC detection panel to quantitate minimal residual disease (MRD) in patients on treatment for AML.
Impact There is a patent filed. Becton Dickinson has paid for the option to have first rights to licence. Data is not yet mature for publication. This is multidisciplinary. It involves clinical colleagues, industry, and the laboratories in Oxford and Stanford.
Start Year 2010
 
Description Collaboration with the company Becton Dickinson 
Organisation Stanford University
Department Stem Cell Institute Stanford
Country United States 
Sector Academic/University 
PI Contribution We identified novel LSC surface antigens. We designed the panel. Both of these were done in collaboration with our colleagues in Stanford. We have tested the panel. We are obtaining data on patients undergoing treatment in the UK AML trials.
Collaborator Contribution The company has developed a new series of monoclonal antibody reagents for FACS-based detection of leukaemic stem cells (LSC) based on our data and data in the field. We are evaluating the commercial possibility of using a FACS-based LSC detection panel to quantitate minimal residual disease (MRD) in patients on treatment for AML.
Impact There is a patent filed. Becton Dickinson has paid for the option to have first rights to licence. Data is not yet mature for publication. This is multidisciplinary. It involves clinical colleagues, industry, and the laboratories in Oxford and Stanford.
Start Year 2010
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Barts Health NHS Trust
Department Department of Haematology
Country United Kingdom 
Sector Hospitals 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Cardiff University
Department Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Queen Elizabeth Hospital Birmingham
Country United Kingdom 
Sector Hospitals 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Development of novel therapeutic anti-leuakemia stem cell antibodies 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution We lead the UK component of this transatlantic collaboration. The basic science and translational studies are driven from Oxford.
Collaborator Contribution It has provided access to novel technologies and unpublished dataAccess to novel therapies. Access to patient samples. Access to laboratory collaborations. Acquisition of biological samples and clinical data. Acquisition of biological samples and clinical data
Impact Grants 2009 £2.2 M MRC Disease Team Award Publications (PubMed ID numbers below): 19664981 19546437 19644143
Start Year 2007
 
Description Downs Syndrome associated preleukaemia and leukaemia 
Organisation Imperial College London
Department Centre for Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the majority of the research effort in this collaborative programme. We study the molecular and cellular basis of leukaemia using patient samples and mouse models that we are generating.
Collaborator Contribution We have a joint programme of work including a joint LLR Programme grant
Impact Grants 2008 Leukaemia Research 5-year Programme Grant, £1.03 M Publications (PubMed ID below): 19594743 18242315 18689547 18059480 18625887 17804520 17644747 17224656 17064858
Start Year 2006
 
Description Genome editing of primary human haemopoietic stem/progenitor populations for treatment of inherited anaemias 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Purification of human haemopoietic stem cells. Functional characterisation of haemopoietic stem cells. Testing of gene edited cells.
Collaborator Contribution Higgs - dissection of alpha globin locus
Impact MRC Discovery Award
Start Year 2015
 
Description Identification of antigenic and immune determinants of graft versus leukaemia in allogeneic stem cell transplantation 
Organisation Cardiff University
Department Division of Population Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I have organised this programme. Aim is to use WGS of AML samples, to identify AML specific variants, contrast this with donor specific exome to identify variants mis-matched between patient and donor, identify mismatched peptides expressed on AML cells that would be recognised by donor and understand the biology of an antigen-specific GvL response.
Collaborator Contribution Partners are contributing to the immune-specific components of the programme.
Impact No outputs yet
Start Year 2016
 
Description Identification of antigenic and immune determinants of graft versus leukaemia in allogeneic stem cell transplantation 
Organisation University College London
Department Biomaterials & Tissue Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution I have organised this programme. Aim is to use WGS of AML samples, to identify AML specific variants, contrast this with donor specific exome to identify variants mis-matched between patient and donor, identify mismatched peptides expressed on AML cells that would be recognised by donor and understand the biology of an antigen-specific GvL response.
Collaborator Contribution Partners are contributing to the immune-specific components of the programme.
Impact No outputs yet
Start Year 2016
 
Description Identification of antigenic and immune determinants of graft versus leukaemia in allogeneic stem cell transplantation 
Organisation University of Birmingham
Department Institute of Metabolism and Systems Research (IMSR)
Country United Kingdom 
Sector Academic/University 
PI Contribution I have organised this programme. Aim is to use WGS of AML samples, to identify AML specific variants, contrast this with donor specific exome to identify variants mis-matched between patient and donor, identify mismatched peptides expressed on AML cells that would be recognised by donor and understand the biology of an antigen-specific GvL response.
Collaborator Contribution Partners are contributing to the immune-specific components of the programme.
Impact No outputs yet
Start Year 2016
 
Description Identification of antigenic and immune determinants of graft versus leukaemia in allogeneic stem cell transplantation 
Organisation University of Oxford
Department Radcliffe Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I have organised this programme. Aim is to use WGS of AML samples, to identify AML specific variants, contrast this with donor specific exome to identify variants mis-matched between patient and donor, identify mismatched peptides expressed on AML cells that would be recognised by donor and understand the biology of an antigen-specific GvL response.
Collaborator Contribution Partners are contributing to the immune-specific components of the programme.
Impact No outputs yet
Start Year 2016
 
Description Investigation of leukaemic Stem Cell biology in Childhood AML 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have fractionated LSC from childhood AML samples. We are studying the molecular and genetic heterogeneity.
Collaborator Contribution They have studied gene expression programmes ad are developing vectors to introduce nucleic acid sequences into LSCs.
Impact No outputs yet.
Start Year 2011
 
Description LSC surface antigen detection and generation of antibodies for diagnostic and therapuetic purposes 
Organisation Stanford University
Department Stem Cell Institute Stanford
Country United States 
Sector Academic/University 
PI Contribution We have identified candidate antigens on leukaemic stem cells (LSC) in Acute Myeloid Leukaemia (AML). We test the utility of antibodies to these antigens to detect AML LSC.
Collaborator Contribution Sharing of reagents. Developing new antibodies for therapeutic and diagnostic purposes.
Impact Shared new reagents. We have a Patent applied for. We have MTAs with becton Dickinson, Stanford University, University of Birmingham. Joint collaboration with Becton Dickinson and Stanford University.
Start Year 2010
 
Description MLL-AF9 acute myeloid leukaemia 
Organisation Medical Research Council (MRC)
Department MRC Molecular Haematology Unit
Country United Kingdom 
Sector Public 
PI Contribution I will be joint principal supervisor on this project to study MLL Gene targets in AML.
Collaborator Contribution My partner Dr Milne will be co-joint supervisor
Impact No outputs yet
Start Year 2014
 
Description Mutant IDH inhibition therapy in AML. 
Organisation Agios Pharmaceuticals
PI Contribution Mutant IDH inhibition therapy in AML. Understanding mechanisms of response and resistance to targeted IDH inhibitor therapy in AML
Collaborator Contribution Contributed samples and intellectual input
Impact Grant income - 2015-2017 Celgene Fellowship in Myeloid Malignancy £423 141 Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia Eytan M. Stein, MD1*, Courtney D. DiNardo, MD2*, Daniel A. Pollyea, MD, MS3, Amir T. Fathi, MD4, Gail J. Roboz, MD5, Jessica K. Altman, MD6, Richard M. Stone, MD7, Daniel J. DeAngelo, MD, PhD7, Ross L. Levine, MD1, Ian W. Flinn, MD, PhD8, Hagop M. Kantarjian, MD2, Robert Collins, MD9, Manish R. Patel, MD10, Arthur E. Frankel, MD6, Anthony Stein, MD11, Mikkael A. Sekeres, MD, MS12, Ronan T. Swords, MD, PhD13, Bruno C. Medeiros, MD14, Christophe Willekens, MD15, Paresh Vyas, MD16,Alessandra Tosolini, BS17, Qiang Xu, PhD17, Robert D. Knight, MD17, Katharine E. Yen, PhD18, Sam Agresta, MD18, Stéphane De Botton, MD, PhD15†, and Martin S. Tallman, MD1† Submitted. Enasidenib Induces Acute Myeloid Leukemia Cell Differentiation to Promote Clinical Response Michael D. Amatangelo1†, Lynn Quek2†, Alan Shih3†, Eytan M. Stein3, Mikhail Roshal3, Stephane de Botton4, Benoit Marteyn5, Noushin Rahnamay Farnoud6, Muriel David7, Katharine E. Yen8, Martin S. Tallman3, Elli Papaemmanuil6,9, Virginie Lacronique-Penard4, Anjan Thakurta1*, Paresh Vyas2*, Ross L. Levine3,6,10* Submitted.
Start Year 2015
 
Description Mutant IDH inhibition therapy in AML. 
Organisation Celgene
Country United States 
Sector Private 
PI Contribution Mutant IDH inhibition therapy in AML. Understanding mechanisms of response and resistance to targeted IDH inhibitor therapy in AML
Collaborator Contribution Contributed samples and intellectual input
Impact Grant income - 2015-2017 Celgene Fellowship in Myeloid Malignancy £423 141 Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia Eytan M. Stein, MD1*, Courtney D. DiNardo, MD2*, Daniel A. Pollyea, MD, MS3, Amir T. Fathi, MD4, Gail J. Roboz, MD5, Jessica K. Altman, MD6, Richard M. Stone, MD7, Daniel J. DeAngelo, MD, PhD7, Ross L. Levine, MD1, Ian W. Flinn, MD, PhD8, Hagop M. Kantarjian, MD2, Robert Collins, MD9, Manish R. Patel, MD10, Arthur E. Frankel, MD6, Anthony Stein, MD11, Mikkael A. Sekeres, MD, MS12, Ronan T. Swords, MD, PhD13, Bruno C. Medeiros, MD14, Christophe Willekens, MD15, Paresh Vyas, MD16,Alessandra Tosolini, BS17, Qiang Xu, PhD17, Robert D. Knight, MD17, Katharine E. Yen, PhD18, Sam Agresta, MD18, Stéphane De Botton, MD, PhD15†, and Martin S. Tallman, MD1† Submitted. Enasidenib Induces Acute Myeloid Leukemia Cell Differentiation to Promote Clinical Response Michael D. Amatangelo1†, Lynn Quek2†, Alan Shih3†, Eytan M. Stein3, Mikhail Roshal3, Stephane de Botton4, Benoit Marteyn5, Noushin Rahnamay Farnoud6, Muriel David7, Katharine E. Yen8, Martin S. Tallman3, Elli Papaemmanuil6,9, Virginie Lacronique-Penard4, Anjan Thakurta1*, Paresh Vyas2*, Ross L. Levine3,6,10* Submitted.
Start Year 2015
 
Description Mutant IDH inhibition therapy in AML. 
Organisation Gustave-Roussy Institute
Country France 
Sector Multiple 
PI Contribution Mutant IDH inhibition therapy in AML. Understanding mechanisms of response and resistance to targeted IDH inhibitor therapy in AML
Collaborator Contribution Contributed samples and intellectual input
Impact Grant income - 2015-2017 Celgene Fellowship in Myeloid Malignancy £423 141 Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia Eytan M. Stein, MD1*, Courtney D. DiNardo, MD2*, Daniel A. Pollyea, MD, MS3, Amir T. Fathi, MD4, Gail J. Roboz, MD5, Jessica K. Altman, MD6, Richard M. Stone, MD7, Daniel J. DeAngelo, MD, PhD7, Ross L. Levine, MD1, Ian W. Flinn, MD, PhD8, Hagop M. Kantarjian, MD2, Robert Collins, MD9, Manish R. Patel, MD10, Arthur E. Frankel, MD6, Anthony Stein, MD11, Mikkael A. Sekeres, MD, MS12, Ronan T. Swords, MD, PhD13, Bruno C. Medeiros, MD14, Christophe Willekens, MD15, Paresh Vyas, MD16,Alessandra Tosolini, BS17, Qiang Xu, PhD17, Robert D. Knight, MD17, Katharine E. Yen, PhD18, Sam Agresta, MD18, Stéphane De Botton, MD, PhD15†, and Martin S. Tallman, MD1† Submitted. Enasidenib Induces Acute Myeloid Leukemia Cell Differentiation to Promote Clinical Response Michael D. Amatangelo1†, Lynn Quek2†, Alan Shih3†, Eytan M. Stein3, Mikhail Roshal3, Stephane de Botton4, Benoit Marteyn5, Noushin Rahnamay Farnoud6, Muriel David7, Katharine E. Yen8, Martin S. Tallman3, Elli Papaemmanuil6,9, Virginie Lacronique-Penard4, Anjan Thakurta1*, Paresh Vyas2*, Ross L. Levine3,6,10* Submitted.
Start Year 2015
 
Description Mutant IDH inhibition therapy in AML. 
Organisation Memorial Sloan Kettering Cancer Center
Country United States 
Sector Academic/University 
PI Contribution Mutant IDH inhibition therapy in AML. Understanding mechanisms of response and resistance to targeted IDH inhibitor therapy in AML
Collaborator Contribution Contributed samples and intellectual input
Impact Grant income - 2015-2017 Celgene Fellowship in Myeloid Malignancy £423 141 Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia Eytan M. Stein, MD1*, Courtney D. DiNardo, MD2*, Daniel A. Pollyea, MD, MS3, Amir T. Fathi, MD4, Gail J. Roboz, MD5, Jessica K. Altman, MD6, Richard M. Stone, MD7, Daniel J. DeAngelo, MD, PhD7, Ross L. Levine, MD1, Ian W. Flinn, MD, PhD8, Hagop M. Kantarjian, MD2, Robert Collins, MD9, Manish R. Patel, MD10, Arthur E. Frankel, MD6, Anthony Stein, MD11, Mikkael A. Sekeres, MD, MS12, Ronan T. Swords, MD, PhD13, Bruno C. Medeiros, MD14, Christophe Willekens, MD15, Paresh Vyas, MD16,Alessandra Tosolini, BS17, Qiang Xu, PhD17, Robert D. Knight, MD17, Katharine E. Yen, PhD18, Sam Agresta, MD18, Stéphane De Botton, MD, PhD15†, and Martin S. Tallman, MD1† Submitted. Enasidenib Induces Acute Myeloid Leukemia Cell Differentiation to Promote Clinical Response Michael D. Amatangelo1†, Lynn Quek2†, Alan Shih3†, Eytan M. Stein3, Mikhail Roshal3, Stephane de Botton4, Benoit Marteyn5, Noushin Rahnamay Farnoud6, Muriel David7, Katharine E. Yen8, Martin S. Tallman3, Elli Papaemmanuil6,9, Virginie Lacronique-Penard4, Anjan Thakurta1*, Paresh Vyas2*, Ross L. Levine3,6,10* Submitted.
Start Year 2015
 
Description Role of cohesin mutations in AML 
Organisation University of Oxford
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We will study the haemopoietic phenotype of heterozygous loss of Rad21 and the haemopietic phenotype of combined Gata1s mutation and Rad21 heterozygous state. If there is a phenotype, we will define the mechanism for the phenotype.
Collaborator Contribution They are supplying critical reagents and their understanding of Rad21 function.
Impact There have been no outputs yet
Start Year 2014
 
Description Single cell heterogeneity on normal human stem and progenitor cells 
Organisation Medical Research Council (MRC)
Department MRC Molecular Haematology Unit
Country United Kingdom 
Sector Public 
PI Contribution We have isolated primary human haemopoietic stem cell populations and are performing RNA-sequencing to begin to define the heterogeneity of these cells.
Collaborator Contribution Providing RNA-seq protocols. We will jointly analyse the data. We will jointly design follow-on functional experiments.
Impact Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors at the single cell level Dimitris Karamitros1,2¶, Bilyana Stoilova1,2¶, Zahra Aboukhalil1, Andreas Reinisch3, Fiona Hamey4, Marina Samitsch1, Lynn Quek1,2,5, Georg Otto1, Emmanouella Repapi1, Jessica Doondea1,2, Batchimeg Usukhbayar1,2, Julien Calvo6, Stephen Taylor1, Nicolas Goardon1, Emmanuelle Six7, Francoise Pflumio6, Catherine Porcher1, Ravindra Majeti3, Berthold Gottgens4, Paresh Vyas1,2,5* Nature Immunology Invited Revision.
Start Year 2014
 
Description WGS and additional biologic studies of haem tumours. 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Design of the program of WGS and integrated multi-"omic" reseatch program on AML UK NCRI AML clinical trial samples to define clonal structures in human AML and how they change in response to therapy. To determine molecular and cellular mechanisms of therapy resistance.
Collaborator Contribution University of Oxford - Lead of AML GECIP (Vyas) and overall haem GECIP (Schuh) University of Cardiff - Sponsor of Trial
Impact Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, Burnett A, Knapper S. The targeted histone deacetylas inhibitor tefinostst (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget. 2016 Feb 25. doi: 10.18632/oncotarget.7692. PMID: 26934551 Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths, M, Solomon E, McCaughan F, Linch D, Gale R, Vyas P, Freeman S, Russell N, Burnett, A and Grimwade D, for the UK National Cancer Research Institute AML Working Group. Assessment of Minimal Residual Disease in Standard Risk AML. NEJM 374 p422-33. (2016). PMID: 26789727
Start Year 2015
 
Description WGS and additional biologic studies of haem tumours. 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Design of the program of WGS and integrated multi-"omic" reseatch program on AML UK NCRI AML clinical trial samples to define clonal structures in human AML and how they change in response to therapy. To determine molecular and cellular mechanisms of therapy resistance.
Collaborator Contribution University of Oxford - Lead of AML GECIP (Vyas) and overall haem GECIP (Schuh) University of Cardiff - Sponsor of Trial
Impact Zabkiewicz J, Gilmour M, Hills R, Vyas P, Bone E, Davidson A, Burnett A, Knapper S. The targeted histone deacetylas inhibitor tefinostst (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias. Oncotarget. 2016 Feb 25. doi: 10.18632/oncotarget.7692. PMID: 26934551 Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, Patel Y, Bhudia N, Farah H, Mason J, Wall K, Akiki S, Griffiths, M, Solomon E, McCaughan F, Linch D, Gale R, Vyas P, Freeman S, Russell N, Burnett, A and Grimwade D, for the UK National Cancer Research Institute AML Working Group. Assessment of Minimal Residual Disease in Standard Risk AML. NEJM 374 p422-33. (2016). PMID: 26789727
Start Year 2015
 
Description WT Clinical Training Fellowship 
Organisation University of Oxford
Department Weatherall Institute of Molecular Medicine (WIMM)
Country United Kingdom 
Sector Public 
PI Contribution Intellectual input and experimental design. Supervision of project.
Collaborator Contribution Intellectual input and experimental design. Supervision of project.
Impact Woll PS, Kjällquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, Erlandsson R, Ngara M, Anderson K, Deng Q, Mead AJ, Stenson L, Giustacchini A, Duarte S, Giannoulatou E, Taylor S, Karimi M, Scharenberg C, Mortera-Blanco T, Macaulay IC, Clark SA, Dybedal I, Josefsen D, Fenaux P, Hokland P, Holm MS, Cazzola M, Malcovati L, Tauro S, Bowen D, Boultwood J, Pellagatti A, Pimanda JE, Unnikrishnan A, Vyas P, Göhring G, Schlegelberger B, Tobiasson M, Kvalheim G, Constantinescu SN, Nerlov C, Nilsson L, Campbell PJ, Sandberg R, Papaemmanuil E, Hellström-Lindberg E, Linnarsson S, Jacobsen SE. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 25 p794-808 (2014)
Start Year 2012
 
Title Immunophenotypic detection of AML LSC 
Description Immunophenotypic detection of AML LSC 
IP Reference WO2012085574 
Protection Patent application published
Year Protection Granted 2012
Licensed No
Impact We are developing a commercial product with the company BD
 
Title AG221 AML-005: 
Description A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral A-221 Plus Subcutaneous Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia (AML) Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited. 
URL https://clinicaltrials.gov/show/NCT02677922
 
Title Celgene Aza-AML-001: 
Description Phase 3, Multicenter, Randomized, Open-label, Study Of Azacitidine Versus Conventional Care Regimens For The Treatment Of Older Subjects With Newly Diagnosed Acute Myeloid Leukaemia. Vyas was local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2011
Development Status Closed
Clinical Trial? Yes
Impact Has led to EMA licence for Aza for AML. NICE refused to fund under TA. Celgene will put forward a patient access scheme for UK patients. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012346-23
 
Title Celgene Aza-MDS-001: 
Description A Multicenter, Randomized, Open-Label, Parallel-Group, Phase 3 Trial Of Subcutaneous Azacitidine Plus Best Supportive Care Versus Conventional Care Regimens Plus Best Supportive Care For The Treatment of Myelodysplastic Syndromes (MDS). Vyas is local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Led to licencing of Aza for MDS. NICE approved drug. Now standard of care for this patient group. 
 
Title Celgene MDS003 
Description A Phase 3, Multicenter, Randomized, Double-blind Study To Compare The Efficacy And Safety Of Oral Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care In Subjects With Red Blood Cell Transfusion-dependent Anemia and Thrombocytopenia Due To IPSS Lower-risk Myelodysplastic Syndromes. Vyas is UK national CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This Phase III licencing study will provide clincial dataset that could potential licence oral Azacitidine. 
URL https://clinicaltrials.gov/show/NCT01099267
 
Title Detection of minimal residual disease in AML 
Description We are testing the clinical utility of this product 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact We have developed a new flow cytometric test of measurable residual disease in patients with Acute Myeloid Leukaemia. 
 
Title Evaulation of anti-PD-L1 in high risk MDS and AML. 
Description A Randomized, Multicenter, Open-label, Phase 2 Study Evaluating The Efficacy And Safety of Azacitidine Subcutaneous In Combination with Durvalumab (MEDIA4736) In Previously Untreated subjects With Higher-risk Myelodysplastic Syndromes (MDS) Or In Elderly (= 65 years) Acute Myeloid Leukemia (AML) Subjects Not Eligible For Hematopoietic Stem Cell Transplantation (HSCT). Vyas is local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-003596-30
 
Title IDH2 inhibitor trial 
Description A PHASE 3, MULTICENTER, OPEN-LABEL, RANDOMIZED STUDY COMPARING THE EFFICACY AND SAFETY OF AG-221 (CC-90007) VERSUS CONVENTIONAL CARE REGIMENS IN OLDER SUBJECTS WITH LATE STAGE ACUTE MYELOID LEUKEMIA HARBORING AN ISOCITRATE DEHYDROGENASE 2 MUTATIO International Phase III trial of a first-in-class oral IDH2 inhibitor in Acute Myeloid Leukaemia. Sponsored by Celgene. Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact still awaited. 
URL https://clinicaltrials.gov/show/NCT01915498
 
Title Monitoring AML leukaemic stem cells 
Description We have developed technology to monitor AML LSCs in all patients treated in UK AML NCRN (National Cancer Regional Network) Trials at diagnosis and following treatment. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact This technology has been transferred to the NHS. 
 
Title Myechild 01 
Description UK NCRI Group Phase III trial of therapy in children with AML. Vyas is lead on AML leukaemic stem cell studies. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2016
Development Status Under active development/distribution
Clinical Trial? Yes
Impact First UK Childhood AMl trial. Vyas is LSC lead 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-005066-30
 
Title Novartis Telesto Trial 
Description A multi-center, randomized, double-blind, placebo- controlled clinical trial of deferasirox in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload (TELESTO) International Phase III trial of an oral iron chelator in Myelodsplastic Syndrome. Sponsored by Novartis. Vyas is UK CI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Impact awaited. Trial data closed and data being analysed. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012418-38
 
Title ROMAZA 
Description Phase 1 trial of Romidepsin plus Azacitidine Combination Therapy In Patients With Newly Diagnosed, Relapsed Or Refractory Acute Myeloid Leukaemia Ineligible For Salvage Chemotherapy. Vyas is co-Investigator and Scientific Lead. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This trial, together with others in the portfolio establish the Bloodwsie funded Therapy Accelration Program (TAP) as the vechicle for early Phase AML and MDS clinical trial delivery through 15 major UK University-NHS teaching hospitals. I am scientific lead of the TAP program and play a leading role in trial design. 
URL http://www.isrctn.com/ISRCTN69211255
 
Title RavVa trial: 
Description Phase II Randomised Trial of 5-Azacitidine versus 5- Azacitidine in combination with Vorinostat in patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes Ineligible for Intensive Chemotherapy). 250 patients. Fully recruited. Vyas is co-Investigator and Scientific Lead. Trial completed. Manuscript submitted. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Closed
Clinical Trial? Yes
Impact This trial is helping to define azacitidine based combination therapies. 
URL http://www.isrctn.com/ISRCTN68224706
 
Title Roche RO504337 in Acute Leukaemia 
Description A Multi-center, Open-label, Phase I Study of Single Agent RO5045337 Administered Orally In patients with Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) In Blast Phase, Or Refractory Chronic Lymphocytic leukemia/Small Cell Lymphocytic Lymphoma (CLL/SCLL). Vyas was local PI. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier 623870
Impact Phase II trials started. 
URL https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-010591-20
 
Title UK AML NCRI Working Group AML 17, AML 18, AML 19 and LI1. 
Description Phase III UK AML trials: AML 19, LI1. Vyas is Lead for Genome England Program and flow cytometric leukaemic stem cell MRD studies. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier AML 17 - 55675535 , AML18 - 31682779 , AMl 19 78449203 , LI1 18218
Impact PV to write 
 
Description Advising LLR to identify and prioritise the needs of blood cancer patients 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 1. Helped fund raising.
2. Helped public awareness
3. Helped improve public advocacy

1. £15 000 were raised.
2. I have been asked to write booklet for patients with Acute Myeloid Leukaemia.
3. I have been asked to give a talk to members of Parliament.
Year(s) Of Engagement Activity 2014
 
Description BBC Oxford Radio Interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Discussion on public access to new drugs made possible by research

Increased local awareness of clinical trials funded by academic funded research
Year(s) Of Engagement Activity 2011
 
Description Fundraising for Leukaemia Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact I spoke to a school assembly. It provoked discussion.

The boys raised £132 for leukaemia research. Several of the boys want to visit the laboratory.
Year(s) Of Engagement Activity 2013
 
Description Interview with television 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I gave a 3 minute interview screened on ITV Central New bulletin at 6 pm and 10 pm.

Public interest in drug trials in leukaemia
Year(s) Of Engagement Activity 2009
 
Description Lynn Quek - Celgene Platform for the Exchange of Expertise and Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk about Translational Research in Haematology at the Celgene Platform the Exchange of Expertise and Research
Year(s) Of Engagement Activity 2016
 
Description Lynn Quek - UK MDS Forum 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk on Differentiation Block in AML at the UK MDS Forum.
Year(s) Of Engagement Activity 2016
 
Description MDS Support group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Multiple talks to a patient support group

Improved patient understanding.
Increased patient advocacy
Year(s) Of Engagement Activity 2013
 
Description NSSG Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talked at meeting for 50 people, mainly an audience of Professional Practitioners and Admin Staff.
Year(s) Of Engagement Activity 2016
 
Description National Science and Engineering Week 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I presented a talk to the public

Three students came to work in the laboratory/hospital in the summer holidays
Year(s) Of Engagement Activity 2013
 
Description Oxford Biomedical Research Centre's annual open day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I organised multiple members to put up stands and displays

Lots of interest from the public
Year(s) Of Engagement Activity 2013
 
Description Oxford and Thames Valley MDS Patient Support Group - Lynn Quek 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Oxford and Thames Valley MDS Patient Support Group and their families/carers visited the WIMM. The visit started with a series of short presentations on current research in haematological cancers at the MRC WIMM, including efforts to improve patient care and recent advances in genomics and stem cell biology. This was followed by a lively Q and A session, and a tour of research facilities.15
Feedback was requested from patients following the event. Feedback was very positive, including the following qyotes I found the meeting and visit very useful. For me, some of the technical stuff (DNA and gene experiments) was rather difficult to follow, but I did understand the general principles of what goes on and why. The presentations were clear and each presenter explained their area of expertise well. All staff were welcoming and pleasant, and the lab tour was also worthwhile.
(John)
I thought it was a great morning at WIMM. The best part for me was undoubtedly the input from Dr Quek and her colleagues, which fascinated both my daughter and me. We talked of little else for the rest of the day and still do! The laboratory visit was also most interesting.
(Rob).
Year(s) Of Engagement Activity 2017
 
Description Public Open Day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 88 members of the general public attended a series of short presentations and Question and Answer session on what benefit research plays in advancing health.

Positive feedback and a request for annual repeat of the session
Year(s) Of Engagement Activity 2010
 
Description Royal Society Summer Science Exhibition - Zahra Aboukhalil 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Hands-on activities, including virtual reality tour of DNA. Huge amount of positive feedback at the time from visitors, engagement with social media posts, collaborative working across department and WIMM.
Year(s) Of Engagement Activity 2017
 
Description Science Week 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Oxford Science Week is held annually to an audience of scientists and the general public.

Good feedback from schools
Year(s) Of Engagement Activity 2006,2007,2008,2009,2014
 
Description Science in the Streets - Zahra Aboukhalil 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Science in the Supermarket, Hands-on activities in supermarket/shopping centres. Good feedback during event, feedback post event included A note to say how good it was to see a stand of yours in Tesco in Aylesbury. To be able to talk to the researchers and to see what they are working on was excellent. It made my day!

Keep it up, and thanks for the bag!
Year(s) Of Engagement Activity 2017
 
Description Student Presentations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Final year students present their work to the members of the Weatherall Institute of Molecular Medicine. This presentation day is held annually.

Improved student training.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description To write a booklet for patients who have AML 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact These booklets and video will be distributed nationally via the LLR.

See above
Year(s) Of Engagement Activity 2014
 
Description Video for patients 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Made a video for patients to explain the symptoms and signs of Myelodysplasia and some of the treatments available

Increased patient awareness
Led in part to the petition to Parliament to reclassify MDS as a cancer
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Wrote a blog post about leukaemia stem cells - Zahra Aboukhalil 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Wrote a blog post about leukaemia stem cells.
Year(s) Of Engagement Activity 2017