A novel anti Wilms-Tumour-1 (WT1) vaccination strategy in haematological malignancy using DNA fusion vaccines deliv

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Scientific Abstract In patients with chronic myeloid leukaemia (CML), while outcome has improved with novel agents such as tyrosine kinase inhibitors, the only curative approach is with allogeneic transplantation. This exerts its benefit through immune control of the cancer, but is only suitable for a small number of patients. This study intends to examine whether DNA vaccination can exert measurable immune control of CML, by assessing disease with the established, clinically relevant monitoring of BCR-ABL transcripts and correlating reduction in BCR-ABL transcript levels (primary endpoint: molecular response rate at 6 months) with responses in WT1 transcript levels and immunological responses (secondary endpoints). We are in clinical testing with a strategy to raise epitope-specific immunity against cancer using a plasmid-DNA fusion vaccine platform. The unique design encodes an immune alert domain (DOM) from tetanus, linked to a tumour antigen-derived epitope (p-DOM-epitope). In the laboratory this design confers tumour protection, breaks immunological tolerance, and induces strong and durable cytotoxic CD8+ T cell immune responses, superior to peptide vaccines. In patients with prostate cancer, 60% (19/31) developed vaccine induced PSMA (prostate specific membrane antigen) specific T cells with excellent vaccine safety. In this same trial a novel delivery system (intramuscular electroporation) enhanced immune responses to the DNA vaccine. We now wish to show that DNA fusion vaccination can control haematological malignancies, specifically CML. Here, escape from cytotoxic T cell attack by loss of MHC I molecules is less likely and molecular markers are already used to guide clinical management. We intend to exploit the high expression of the WT1 antigen in CML and build on the observation that in spite of inducing only transient immunity, even the suboptimal vaccination with peptide vaccines against WT1 conferred some clinical benefit. Our strategy is to use double DNA vaccination targeting two separate WT1-derived peptides. In this phase I/II study we propose to vaccinate up to 37 HLA A0201+ patients with CML in cytogenetic remission (CCyR), stable on imatinib, with 6x 1-monthly doses of two WT1 vaccines, followed by maintenance vaccination up to 2 years in responders. As the vaccine can only work by stimulating the immune system, we intend to show that molecular clinical responses are related to a CD8+ T cell response induced by vaccination, measured by tetramer and ELISPOT analysis. Synchronously, a consented control group of up to 55 patients will be recruited, who are found to be HLA A2 negative at screening (genetic randomiztion). The generated data will assess the clinical response rate, validate WT1 measurement by qPCR as a biomarker for vaccine responses in CML and inform whether definitive Phase III testing of the vaccine is warranted. We expect to recruit 1-2 HLA A0201+ and 2-3 HLAA2- patients/ month with a follow up of 24 months, allowing completion of the study in the 4 years of funding requested.
 
Description A randomised discontinuation trial to evaluate optimal duration of anti-PD1 monoclonal antibody treatment in patients with metastatic melanoma
Amount £100,000 (GBP)
Funding ID HTA/15/57/66 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start  
 
Description CTAP funding (Leukemia and Lymphoma Research)
Amount £284,857 (GBP)
Organisation Leukaemia and Lymphoma Research 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
End 09/2014
 
Description Cancer Research Uk, Accelerator Award - Success determinants and mechanisms of immunotherapy
Amount £3,899,500 (GBP)
Funding ID 21998 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2022
 
Description Immunotherapy for head and neck cancer.
Amount £406,000 (GBP)
Funding ID MR/P013414/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 12/2018
 
Description MICA: Immunotherapy for oral cancer prevention and treatment
Amount £600,000 (GBP)
Funding ID MR/P024351/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 09/2019
 
Description Project Grant (Meso)
Amount $50,000 (USD)
Organisation Mesothelioma Applied Research Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2014 
End 12/2015
 
Description BMS Satelite Symposium Immunotherapy in Cancer a primer 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Sparked questions and discussion afterwards.
Year(s) Of Engagement Activity 2014
 
Description British Thoracic Oncology Group (BTOG), Jan 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description British Thoracic Oncology Group Jan 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2016
 
Description CR UK Lab Tour Oct 2012 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Science Talk and lab demos for Cr UK Supporters - October 2012 - 30 legacy supporters

impact unknown
Year(s) Of Engagement Activity 2012
 
Description Cancer Care Study Day - Advances in Melanoma, November 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Speaker at Cancer Care Study Day - Advances in Melanoma, November 2016
Year(s) Of Engagement Activity 2016
 
Description Cancer Immunology Campaign Tour Sept 2014 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Presentation and tour for potential donors for the Cancer Immunology Centre Campaign

improved understanding of the project for potential donors
Year(s) Of Engagement Activity 2014
 
Description Gene Vaccination Conference, Ascoli, Italy Oct 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact talk sparked questions and discussions afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Immuno-Oncological Network Ghent Kickoff meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I gave a keynote lecture at the inaugural meeting of the immuno-oncology network in Ghen, Belgium. this intends to bring together diverse activities in the immunology and oncology space into a coherent whole for added benefit for the different parties. This included the Belgian cancer charity, industry collaborators and the meeting reached out to national media
Year(s) Of Engagement Activity 2016
 
Description Immunostimulatory monoclonal antibodies and immunomodulation: harvesting the crop - Pamploma - Oct 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description International Cancer Immunolgy Conference, New York, Sept 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description International Symposium on Malignant Mesothelioma, Bethesda, USA, March 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Interview on Victoria Derbyshire Programme (BBC) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed with Trial Patient about immunotherapy trials.
Year(s) Of Engagement Activity 2018
 
Description Lung Cancer Advisory Board - Augusr 2015 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Provided input and advice
Year(s) Of Engagement Activity 2015
 
Description Media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Print and radio interviews; press release. Picked up extensively by national media (Scotland) and industry but also general media around the world.
Year(s) Of Engagement Activity 2016,2017
 
Description Molecular Biology in Cancer Workshop, Birmingham, May 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Occular Melanoma Conference, Reading Sept 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Oncology Forum, Manchester June 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description PLANETS Annual NET Patient Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Invited Speaker at the Annual Patient Meeting.
Year(s) Of Engagement Activity 2017
 
Description Pembrolizumab Advisory Board May 2015 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Presentation at Cancer Vaccines Conference, London Sept 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact talk sparked questions and discussions afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Presentation at Cancer Vaccines Conference, London Sept 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact talk sparked questions and discussions afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Presentation at European Pancreatic Conference, Southampton June 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked questions and discussion afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Presentation at OcuMel Conference London Sept 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk sparked questions and discussion afterwards.

not known
Year(s) Of Engagement Activity 2013
 
Description Presentation at Oncology Forum, Manchester April 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Talk sparked questions and discussion afterwards.

unknown
Year(s) Of Engagement Activity 2013
 
Description Presentation at South West Melanoma Forum, Swindon Sept 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact talk sparked questions and discussions afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Presentation to NIHR Patient Liaison Group by Gareth Thomas June 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact talk sparked questions and discussion afterwards

support for continued work
Year(s) Of Engagement Activity 2014
 
Description RICS Annual Dinner, January 2016 
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 Gave brief talk about the new centre, raised money to support the campaign and generated interest in the Campaign
Year(s) Of Engagement Activity 2016
 
Description Regioanl Lung Cancer Clinical Trial Investigators Meeting, Southampton June 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact talk sparked questions and discussion afterwards

unknown
Year(s) Of Engagement Activity 2014
 
Description Royal Marsden Lung Cancer Symposium, London, November 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015
 
Description Science Communications Meeting March 2103 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Meeting CR UK science communications teams to provide research updates for use in public- facing comms including CR UK website science blog and presentation information.

Provided research updates for use in public- facing comms including CR UK website science blog and presentation information.
Year(s) Of Engagement Activity 2014
 
Description TV Production Consultation March 2014 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Consultation meetings in March 2014 with production company Maverick TV in planning of a feature length TV dram focussing on cancer research in partnership with CR UK

unknown
Year(s) Of Engagement Activity 2014
 
Description UHS NHS Website March 2013 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Public facing profile webpage detailing clinical research projects into cancer in UHS in partnership with CR UK Southampton Centre

Page view state not available
Year(s) Of Engagement Activity 2013
 
Description University of Edinburgh Seminar - Genomic evaluation of tumour infiltrating immune cells - Feb 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2016
 
Description Wessex Lung Cancer Meeting, Bournemouth April 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact talk sparked questions and discussion afterwards
Year(s) Of Engagement Activity 2015