Novel targeted contrast agent for early detection of brain metastasis: from animal to patient

Lead Research Organisation: University of Oxford
Department Name: CRUK/MRC Oxford Inst for Radiation Oncol

Abstract

Metastasis is the spread of cancer from the initial site, e.g. breast or lung, to another part of the body. Metastasis to the brain is one of the most feared complications of cancers such as breast and lung, as they cannot be detected at a stage when they can be treated and life expectancy once diagnosed is generally only a few months. Magnetic resonance imaging (MRI) is widely used for diagnosing brain cancer, but the techniques are only sensitive to tumours that are large and well advanced. These MRI methods use so-called contrast agents, which can be thought of as dyes that alter the colour or intensity of the images in the areas where they are present. Until now the contrast agents used in cancer diagnosis have been passive in that they require major damage to the brain blood vessels to allow their passive accumulation within the tumour. As a result, treatments that might have been successful at earlier stages do not work, because the disease is too far advanced. To overcome this problem, we have been developing a new type of MRI contrast agents that will actively bind to specific molecules associated with disease, and identify areas where levels of these molecules are increased. We have found that the levels of certain molecules on the blood vessels in the brain are increased early in the development of brain disease. In particular, we have identified specific molecules that are increased in the early stages of brain metastasis. By designing contrast agents that will bind to these specific molecules, we believe that we have found a way of detecting early brain metastasis when it cannot otherwise be seen. We have already shown that our targeted contrast agent works in mouse models of brain metastasis. The first aim of this project, therefore, is to take our agent and convert it to a form that will work in humans. We will then test this humanised form of the agent both for detection of the target human molecule and for any potentially harmful or toxic effects. When we have completed the work in this proposal, the humanised contrast agent will be taken forward into a clinical trial. We believe that our approach will greatly improve our ability to diagnose brain metastases in the early stages and, as a result, change the way in which patients with this currently incurable disease are treated and managed.

Technical Summary

Metastatic spread of a primary tumour to the brain remains one of the greatest hurdles in cancer therapy, and prognosis is poor. Magnetic resonance imaging (MRI) is commonly used for the diagnosis of brain cancer, but current, gadolinium-enhanced techniques are sensitive only to larger, late stage tumours ( 5mm), when therapeutic potential is limited. Our approach, capable of detecting 200um tumours, will enable much earlier detection of brain metastases. We have developed targeted MRI contrast agents, which detect specific molecules expressed early in disease. We have shown that our new patent-protected contrast agent, targeting the endovascular adhesion molecule VCAM-1, enables early detection of metastases in mouse brain when they are undetectable by existing clinically-used methods. Importantly, we have also demonstrated expression of VCAM-1 in human post-mortem brain tissue containing micrometastases. We believe that early diagnosis of brain metastases using our contrast agent will increase therapeutic options and change clinical management of a substantial number of cancer patients. Our aim here is to fully humanise the targeting anti-VCAM-1 antibody and to take the humanised contrast agent through preclinical and toxicological testing, prior to clinical trials. Our approach has already generated considerable interest amongst both Oncologists and Imaging Companies.

Publications

10 25 50
 
Description MSc in Radiation Oncology - Module on Imaging
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Medical Sciences Division Graduate Studies Committee
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
 
Description NC3Rs/MRC CRACK IT Review Panel A
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Trainee Sub-Committee: International Society for Magnetic Resonance in Medicine
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description EPSRC Programme Grant
Amount £7,922,968 (GBP)
Funding ID EP/L024012/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 07/2014 
End 06/2019
 
Description MRC DPFS
Amount £2,600,000 (GBP)
Funding ID MR/K015443/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 03/2018
 
Title VCAM-ab 
Description Humanised anti-VCAM-1 antibody 
Type Of Material Antibody 
Provided To Others? No  
Impact None to date 
 
Description Image guided brain metastasis study 
Organisation The Walton Centre
Country United Kingdom 
Sector Hospitals 
PI Contribution We have assessed inflammatory signatures in samples from the invasive edges of brain metastases in patients identified by image guidance at The Walton Centre.
Collaborator Contribution Our collaborators at The Walton Centre have provided imaging data and biopsy samples.
Impact Two primary publications (2016 and 2019) - doi: 10.18632/oncotarget and doi: 10.1158/1078-0432.CCR-18-1889
Start Year 2014
 
Description Imaging CAM expression in brain tumours 
Organisation University of Portsmouth
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of models with knockdown tumour cell lines from Portsmouth and imaging of these with our molecular MRI contrast agents.
Collaborator Contribution Provision of knockdown tumour cell lines
Impact None yet. Multi-disciplinary - biology, physics/imaging
Start Year 2015
 
Description VCAM-targeted MRI in neurological disease 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of VCAM-MPIO contrast agent and SOPs for synthesis and use in animal models.
Collaborator Contribution Applying the VCAM-MPIO in models of dementia.
Impact None yet Multi-disciplinary - biology, physics/imaging, chemistry
Start Year 2015
 
Title ANTIBODIES AGAINST CD106 (VCAM-1) 
Description The invention provides an antibody or fragment thereof that specifically binds to human endothelial vascular cell adhesion molecule- 1 (VCAM-1), wherein the antibody or fragment thereof binds to the extracellular domain of VCAM-1, and wherein the antibody or fragment thereof binds to VCAM-1 when expressed on endothelial cells, wherein the antibody or fragment thereof is a human or humanized antibody, or fragment thereof. 
IP Reference WO2013160676 
Protection Patent application published
Year Protection Granted 2013
Licensed No
Impact N/A
 
Title MULTIMERIC PARTICLES 
Description The invention provides multimeric particle comprising metal-containing particles covalently bonded to one another by linker groups wherein at least some of said linker groups are cleavable. The invention further provides a contrast agent comprising said multimeric particles, along with a method of improving contrast of an image using said contrast agent. 
IP Reference WO2008035069 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact None yet
 
Title huVCAM-mMPIO 
Description huVCAM-mMPIO is a novel MRI contrast agent that enables early detection of secondary cancer in the brain. Currently under scale up for cGMP production and Phase I/II1 clinical trial. Funding MRC DPFS Biocatalyst Scheme. 
Type Diagnostic Tool - Imaging
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2018
Development Status Actively seeking support
Impact Press releases and media coverage in developmental stages. 
 
Description CRUK Lab Tour Open Day 
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 Public/other audiences
Results and Impact Several Corporate funders and research nurses attended the visit, and were very interested to learn about our current research into brain metastasis and how we hope to move this into the clinic shortly.

I was contacted afterwards by one of the research nurses describing their interest in our work.
Year(s) Of Engagement Activity 2014
 
Description MSc and DTC Lectures 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Regular lectures on brain imaging in cancer and neurosciences to Doctoral Training Course and M.Sc. students, which sparked questions and discussion as well as interest in entering research within this field of research. Outcome is often one or more students joining the group for either M.Sc. or D.Phil. projects.

Development of collaborations and numerous examples of interest in applying our VCAM-targeted technology in different patients groups from paediatrics to head injury.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Mercedes Family Day 
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 Manned a stall at the Mercedes family day for CRUK, explaining aspects of cancer research within the Institute. Lots of people participated and were very engaged and interested in the research being done.
Year(s) Of Engagement Activity 2017
 
Description Oxford Cancer Research Center Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 60 school children attended the open day at which we had a stand describing our work in taking our VCAM-targeted MRI contrast agent to clinical trial.

Feedback indicated a high degree of interest and enthusiasm for the science, with several children inspired to consider science as a career.
Year(s) Of Engagement Activity 2012
 
Description Oxford Cancer Research Center Open Evening 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 100 members of the public, including cancer patients and CR-UK supporters, attended the open day at which we had a stand describing our work in taking our VCAM-targeted MRI contrast agent to clinical trial.

Feedback indicated a high degree of interest and enthusiasm for the technology and advance in cancer diagnosis presented.
Year(s) Of Engagement Activity 2012
 
Description Radio interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A description of our research and short exerts from the interview were broadcast on several news bulletins throughout the morning on BBC Radio Oxford and Jack FM.

A member of the public contacted us afterwards to ask if our treatment was ready for use, as his wife was suffering from brain tumours.
Year(s) Of Engagement Activity 2012
 
Description Staff talk for CRUK at Mercedes-Benz Grand Prix 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation of CRUK funded work at Mercedes-Benz as CRUK is their nominated charity. Many of the audience (approx 100) found resonance with the topic (brain cancer) and commented afterwards that they were interested and excited to hear what research is being done.
Year(s) Of Engagement Activity 2017
 
Description Teachers workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Approximately 20 teachers attended the workshop and were provided with various tools for introducing the topic of cancer and brain imaging into their curricular activities.

Further interaction with some of the schools involved, and requests for school visits.
Year(s) Of Engagement Activity 2013