Development ofTherapeutic Antibodies Targeting Human Acute Myeloid Leukemia Stem Cells

Lead Research Organisation: University of Oxford
Department Name: Weatherall Inst of Molecular Medicine

Abstract

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Technical Summary

Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow with strong
evidence for the critical involvement of self-renewing leukemia stem cells (LSC) in disease
pathogenesis. We and others have proposed that AML LSC must be eradicated to achieve cure,
yet these cells are resistant to standard chemotherapy and radiation treatments. Our approach
to the development of novel AML therapeutics is to produce therapeutic antibodies directed
against cell surface antigens preferentially expressed on clinically relevant AML stem cells. We
identified and validated LSC-preferential expression of CD47, CD96, CD97, and TIM3 using
antigen-specific monoclonal antibodies. CD47 functions as a ?don?t eat me? signal by binding to
SIRP.. on phagocytic cells and delivering a dominant inhibitory signal. We determined that a
blocking anti-CD47 monoclonal antibody targets and depletes LSC in a mouse
xenotransplantation model by enabling their in vivo phagocytosis and elimination. We propose
to develop a clinical grade therapeutic antibody through the following aims:
(1): To define the surface marker expression of clinically relevant AML LSC in serial bone
marrow samples from patients enrolled in the UK NCRI AML 16 and 17 trials
(2): To develop humanized blocking monoclonal antibodies directed against human CD47
(3): To develop humanized recombinant monoclonal and/or bi-specific antibodies targeting
CD47 in combination with other AML LSC-specific proteins
(4): To develop a GMP grade antibody from the best candidate, including pre-clinical
toxicokinetic studies and large-scale production, and submit an IND filing with the FDA/MHRA

Publications

10 25 50
 
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 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 of Great Britain & Northern Ireland (UK)
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 of Great Britain & Northern Ireland (UK)
Start 06/2012 
End 06/2017
 
Description Celgene PhD Studentship
Amount £174,000 (GBP)
Organisation Celgene 
Sector Private
Country United States of America
Start 09/2010 
End 08/2013
 
Description Haematology and Stem Cell Theme Oxford Biomedical Research Centre (NIHR)
Amount £5,000,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2017 
End 03/2022
 
Description LLR - Leukaemia & Lymphoma Research. CTAP (Clinical Trial)
Amount £308,470 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2015 
End 02/2018
 
Description MRC Clinical Training Fellowship
Amount £233,726 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2014 
End 10/2017
 
Description MRC Molecular Haematology Unit Award
Amount £520,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2013 
End 03/2017
 
Description Oxford BRC - Joint Application
Amount £780,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 03/2017
 
Description Understanding heterogeneity of treatment response in 'standard' risk acute myeloid leukaemia
Amount £19,845 (GBP)
Organisation Bloodwise 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2015 
End 10/2018
 
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 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 Clinical Trial of Anti-CD47 
Organisation Leeds Teaching Hospitals NHS Trust
Department Department of Clinical Haematology
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 of America 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 (BD)
Country United States of America 
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 of America 
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 of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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 Stanford University
Country United States of America 
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 University Hospitals Birmingham NHS Foundation Trust
Department Queen Elizabeth Medical Centre, Birmingham
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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 Epigenetics of Acute Myeloid Leukaemia 
Organisation Celgene
Country United States of America 
Sector Private 
PI Contribution Study of epigenetic changes in Leukaemic stem cells in Acute Myeloid Leukaemia
Collaborator Contribution Access to demethylation agents for experiments
Impact Multidisciplinary collaboration. Involving medicinal chemists and biologists.
Start Year 2010
 
Description Investigation of leukaemic Stem Cell biology in Childhood AML 
Organisation University College London
Department UCL Cancer Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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 of America 
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 WGS and additional biologic studies of haem tumours. 
Organisation Cardiff University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
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 of Great Britain & Northern Ireland (UK) 
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
 
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. 
 
Title Camellia trial 
Description First-in-class Phase I trial of Humanized Monoclonal Antibody anti-CD47 in Acute Myeloid Leukemia. This is an academically funded, 7-year collaboration between my laboratory and Weissman Laboratory Stanford University. Sponsored by Stanford University. Oxford University is Sponsor in the EU. Oxford Oncology Clinical Trials Unit is running this multi-centre UK trial. Trial will complete in 6/2017. Phase II trials planned. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact This first-in-class trial of a new monoclonal therapeutic antibody provides a rare example of academically funded work going from a laboratory observation through to development, manufacture and pre-clinical testing of a clinical therapuetic all the way to first clinical trial within the envelope of an entirely academically funded program. This work is a collaboration between my laboratory, my clinical work in Oxford, the Oxford Clinical Oncology Early phase Trial Unit, the UK AML NCRI Clinical Trial Group and Stanford Unviersity. I am CI of the AML trial. The Stanford PI Dr Weissman has established a spin out company CD47 Inc to take this program further in clinical development. 
 
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. 
 
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. 
 
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 
 
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. 
 
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 
 
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. 
 
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. 
 
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. 
 
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 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 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 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 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 Student Presentations 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Participants in your research and patient groups
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 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