Novel targeted contrast agent for early detection of brain metastasis: from animal to patient stage 2

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 a secondary or different part of the body. Metastasis to the brain is one of the most feared complications of cancers such as breast and lung, as it is rarely detected at a stage when it can be treated, and life expectancy once diagnosed is generally only a few months.

Magnetic resonance imaging (MRI) is widely used for diagnosing brain tumours (cancer). These MRI methods use so-called contrast agents, which can be thought of as dyes that alter the intensity or brightness of the images in the areas where they are present. Until now the contrast agents used in cancer diagnosis have needed major damage to the brain blood vessels to occur before their accumulation within the tumour can be seen in the images. As a result, these methods are only able to detect tumours that are well established, and 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 agent that does not need to accumulate within the tumour via leaky blood vessels. Instead these contrast agents will bind to the surface of the blood vessels that is directly in contact with the blood when certain molecules are present on the vessels.

We have found that the levels of a particular molecule called VCAM-1 are increased on blood vessels that are closely associated with early metastases in the brain. This VCAM-1 expression occurs long before damage to the blood vessels. Using a contrast agent that will bind to VCAM-1, we believe that we have found a way to detect early brain metastases when they cannot otherwise be seen. Under our current MRC DPFS award we have converted our VCAM-1-targeted contrast agent into a form that can be used in humans. We have verified binding of this humanised agent to the target human molecule and will soon start in-depth testing of the agent for any damaging or toxic effects in the body that would prevent its use in man.

Under the current application, therefore, we propose to manufacture the humanised contrast agent to the levels required for human use and to obtain the ethical and regulatory approvals required for human trials. When these approvals are in place, we will undertake a Phase I/IIa clinical trial in cancer patients with known brain metastases. The primary aim of this study will be to assess safety, but it will be designed such that we can also obtain preliminary information as to how effective the contrast agent is in detecting metastases in the brain.

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 devastating disease are treated and managed.

Technical Summary

Metastasis to the brain is one of the most feared complications of systemic cancers, and prognosis is poor. Magnetic resonance imaging (MRI) is widely used for diagnosis of brain cancer, but the techniques are sensitive to late-stage disease when therapeutic potential is limited. Development of targeted MRI contrast agents, which detect specific molecules expressed early in disease, will overcome this limitation. We have demonstrated that our new contrast agent, targeting the endovascular adhesion molecule VCAM-1, enables detection of micrometastases in mouse brain when this pathology is otherwise undetectable. Our current DPFS award is funding us to create a fully humanised and biodegradeable version of our contrast agent, undertake toxicology and scale up the synthetic protocol. We now seek funding for cGMP synthesis of the agent, acquisition of regulatory and ethical approval and a Phase I/IIa trial in solid cancer patients with known brain metastases. In addition to obtaining safety and pharmacokinetic information, we will obtain some preliminary efficacy data thus maximising value of this Phase I/IIa trial.

Planned Impact

The primary beneficiaries of this research are cancer patients at high risk of brain metastasis. A significant proportion of all cancer patients will suffer metastatic spread to the brain. Most brain metastases originate from lung (40-50%), breast (15-25%), melanoma (5-20%), and kidney (5-10%), although the primary site remains unknown in up to 15% of patients.

We anticipate two modes of screening with huVCAM-mMPIO:
(a) Screening at time of primary cancer diagnosis, which will
(i) confirm curative potential of radical therapy for primary when BM are absent,
(ii) enable radical treatment of primary and BM when efficacy is greatest,
(iii) enable decision towards palliative care, when BM are untreatable, improving quality of life.

(b) Periodic screening following treatment of the primary cancer, which will
(i) enable tailored treatment of BM when efficacy is greatest,
(ii) enable decision to palliative care when BM are untreatable,
(iii) prevent unnecessary and debilitating prophylactic treatments when BM are absent.

Refining and increasing management options will increase QALYs overall and reduce costs compared to current gadolinium-based diagnosis. Almost all MRI investigations for brain tumors involve contrast, and we expect ~100,000 UK patients p.a. (~2.5m worldwide) to benefit from huVCAM-mMPIO use. The timescale to the point of patient benefit is likely to be 3-5 years; the current proposal to end of Phase I/IIa trial is 3 years and, if successful, we would anticipate running a full Phase IIb trial soon after that. In this Phase II trial, we would link huVCAM-mMPIO diagnosis of brain metastasis to intervention (e.g. radiotherapy, radiosurgery/surgery), in order to determine efficacy of earlier diagnosis/treatment in limiting symptoms.

Although a limitation to chemotherapy in brain metastases is poor blood-brain barrier (BBB) penetrability, a new generation of therapeutics are in development that circumvent this problem. For example, GRN1005 an LRP-directed peptide-drug conjugate is designed to deliver cytotoxic drug across the intact BBB by exploiting a native transport mechanism. GRN1005 is currently in Phase II trial in breast cancer patients with brain metastases. Similarly, Vorinostat, a histone deactylase inhibitor, has been shown to cross the intact BBB, and is currently in Phase I trial in combination with radiotherapy for the treatment of brain metastases. If successful, such therapeutics could greatly benefit from earlier diagnosis.

At the same time there are many other diseases, both neurological and systemic, with an inflammatory component and for which we anticipate our approach will have clinical application. Moreover, our mMPIO can be targeted with a range of ligands, in addition to our huVCAM antibody. Thus, the production of biocompatible mMPIO, as proposed here, provides a platform for multiple targeting applications across numerous diseases. We expect these additional applications to include multiple sclerosis, atherosclerosis, inflammatory bowel disease, placental inflammation, primary cancers, other secondary cancers, traumatic head injury and transplant rejection. In each of these cases, we have been approached by medical experts in these fields with a view to testing the technology. Once our huVCAM-mMPIO agent has successfully completed the proposed Phase I/IIa trial we will re-engage with these experts and others through the consortium's wide range of expertise (cardiovascular medicine, neurological disease, oncology) with a view to wider clinical application of the agent. It should be noted that RC, Professor of Cardiovascular Medicine and Clinical Director of the Oxford Acute Vascular Imaging Centre, is PI/Co-I of several Phase II trials of drugs targeting vascular inflammation with MRI outputs. Thus, he is ideally placed to translate clinically in these areas.

Publications

10 25 50
 
Description Aeres Evaluation Committee: Institut d'Imagerie Biomédicale CEA-CNRS URA2210, Paris
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Participation in a advisory committee
 
Description Biomedical Scientific Advisory Board: The Brain Tumour Charity
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description British Chapter of the International Society for Magnetic Resonance in Medicine Committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description External Examiner, MSc Advanced Biomedical Imaging, UCL, London
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
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 Neuro-Oncology Strategic Working Group, University of Oxford
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Membership of a guideline committee
 
Description Scientific Advisory Board NORMOLIM; the Norwegian Molecular Imaging Infrastructure
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Scientific Advisory Board: Helmholtz Research Alliance "ICEMED"
Geographic Reach Local/Municipal/Regional 
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
 
Title VCAM-ab 
Description Humanised anti-VCAM-1 antibody 
Type Of Material Antibody 
Provided To Others? No  
Impact None to date 
 
Description Detection of invasive margins in primary brain tumours 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution We are investigating the nature of the invasive margin in primary and secondary brain tumours with a view to improved detection and treatment. We are contributing imaging and in vivo models of brain tumours to this collaboration.
Collaborator Contribution Our partners have contributed patient-derived primary brain tumour cells to this collaboration, for use in our in vivo models.
Impact No outcomes at present. Multidisciplinary - biology, physics, chemistry.
Start Year 2018
 
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 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 Filming/interviewing 
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 Supporters
Results and Impact Interview describing our recent research that was presented at the NCRI conference in 2015. Many people afterwards commented on having seen the YouTube video and were interested to find out more.
Year(s) Of Engagement Activity 2015
 
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 CRUK Laboratory Open Day; corporate supporters and clinical trials staff (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 on our recent work into the early detection of secondary brain tumours. This generated a lot of interest in the audience and considerable discussion afterwards. Both supporters and cancer related practitioners were interested to hear of our advances and how this would impact on clinical care.
Year(s) Of Engagement Activity 2014
 
Description CRUK Trustees Visit (Oxford, March 2016) 
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 Tour of facilities, presentation of research activities and discussion of broader context of CRUK funding and gaps therein.
Year(s) Of Engagement Activity 2016
 
Description Institute for Cancer Research, London (2015) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact TBA
Year(s) Of Engagement Activity 2015
 
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 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 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 TV Interview (That's Oxford TV) 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Media (as a channel to the public)
Results and Impact Interview for local TV network about our recent work presented at the NCRI conference in 2015. A number of friends from the general public noted that they had seen this and were interested in our work.
Year(s) Of Engagement Activity 2015
 
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