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.
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.
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
Perez-Balderas F
(2017)
Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI.
in Nature communications
Description | Aeres Evaluation Committee: Institut d'Imagerie Biomédicale CEA-CNRS URA2210, Paris |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Participation in a guidance/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: Helmholtz Research Alliance "ICEMED" |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Participation in a guidance/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 | Public |
Country | United Kingdom |
Start | 06/2014 |
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 granted |
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 | Advent |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Contributed her images to support our online advent calendar. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.oncology.ox.ac.uk/advent |
Description | Bayer |
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 | Delivered an interactive stand helping visitors to explore the use of MRI in detecting brain metastases as part of a science and medicine careers day hosted by Bayer, Reading. |
Year(s) Of Engagement Activity | 2019 |
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 | 2009,2010,2011,2012,2013,2014,2015,2016 |
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 | School 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 | Schools |
Results and Impact | Delivered an interactive stand helping visitors to explore the use of MRI in detecting brain metastases as part of our Annual Open Day for students aged 15-18. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.oncology.ox.ac.uk/blog/oncology-open-day |
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 |
Description | UNIQ |
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 | Delivered a 90 min workshop on imaging in the context of cancer medicine as part of a Summer School sponsored by the University of Oxford to widen participation and raised STEM aspirations. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.oncology.ox.ac.uk/news/oncology-outreach-supporting-diversity-at-oxford |