Pump Prime Awards
Workshop: Clinical Trial Readiness for CNS Drug Delivery – 8-9 November 2021
On 8-9th November 2021, we held our third workshop, this time specifically focussing on clinical trial readiness for CNS drug delivery.
During this event, we launched a pump prime funding opportunity for projects that will move trial proposals into an advanced state of readiness.
We awarded two pump prime awards, which are detailed below.
Antonios Pouliopoulos, Kings College London
Focused ultrasound for targeted carboplatin delivery in Diffuse Intrinsic Pontine Glioma
Although submitted as part of CBTDDC's 'Clinical Trial Readiness' pump prime opportunity, this project is funded by Abbie’s Army, who partnered with us on this initiative.
Patients with diffuse intrinsic pontine glioma (DIPG) have limited treatment options and poor outcomes, leading to a median survival of 9 months. Most drugs fail partly due to the blood-brain barrier (BBB), which blocks them from entering the brain.Focused ultrasound (FUS) in combination with microbubbles allows targeted and non-invasive BBB opening, thereby increasing the dose delivered to the tumour.
FUS-mediated drug delivery has been tested for over two decades in animal models,and is rapidly translating into the clinic. We have developed a neuronavigation-guided FUS system, which is being used in a phase I trial in DIPG patients in the US (NCT04804709). The US trial aims to enhance delivery of oral panobinostat. Here, we will combine FUS with intravenous carboplatin.
Carboplatin represents an ideal chemotherapy to administer using this technique as paediatric DIPG cells are highly sensitive to carboplatin in vitro at concentrations that are not toxic to normal brain in vivo. Carboplatin has also been shown to increase the median survival of people with DIPG to 15.3 months, when delivered in sufficient concentration into the tumour using convection enhanced delivery.
We have previously tested the FUS system in non-human primates, and have established its radiological, histological and behavioural safety. Regulatory authorities are expected to request additional data with a DIPG model, so this project will use a DIPG mouse model. The aims are to: (1) establish radiographic and histological safety of the system using clinically relevant parameters, (2) demonstrate local control of the disease through MRI, and (3) measure the drug delivery increase and survival benefit compared with control mice. The preclinical evidence we gather from this project will support an MHRA application for our phase I clinical trial.
In this project, we aimed to deliver carboplatin across the blood-brain barrier (BBB) in mice using clinically-relevant focused ultrasound parameters and microbubbles approved for use in the UK.
We showed that:
- BBB opening is feasible using clinically-relevant acoustic parameters and SonoVue microbubbles, which are approved for use in the UK;
- Paediatric DIPG cells are more sensitive to carboplatin treatment than adult GBM cells; and
- FUS-induced BBB opening increased the uptake of intravenously delivered carboplatin in targeted brain regions of three mice.
These results, along with existing pre-clinical and clinical data showing 6-fold increase of carboplatin, will enhance our MHRA application for the first UK clinical trial in paediatric patients with DIPG. We expect to submit this application by Autumn 2023.
Note: Since starting the pump prime project, Antonios has also been awarded £850k from the Little Princess Trust to develop focused ultrasound and thermosensitive liposomes for paediatric brain tumour treatment.
Wenbo Zhan, University of Aberdeen, UK
Optimisation of infusion catheter posture for improving convection-enhanced drug delivery to brain cancer
Convection-enhanced delivery (CED) can effectively bypass the blood-brain barrier. However, its delivery outcomes remain disappointing, mainly due to heterogeneous drug distribution and insufficient drug accumulation. These limitations can largely be attributed to the highly anisotropic brain tissue that is induced by widely distributed axon bundles.
Axons fibres in brain white matter form several cable-like bundles. These bundles present different orientations that vary considerably depending on location in the brain. These bundles can consequently guide the flow of drugs in undesired directions, and thereby reduce drug distribution. Optimising the CED infusion direction and infusion site with respect to local tissue anisotropy is critical to achieving maximal drug coverage of the tumour. This project set out to tackle this challenge through multiphysics modelling.
By identifying the optimal posture of infusion catheter, both in terms of infusion direction and infusion site, this work could enable researchers worldwide to optimise the effectiveness of CED and reduce the risk of failure of CED trials.
We developed a mathematical model for simulating CED, and reconstructed a 3D realistic brain model from patient-specific MR images to enable simulation of the intratumoural environment. Four therapeutic agents were tested in the models, including plain temozolomide, nanoparticle-encapsulated temozolomide, plain paclitaxel and nanoparticle-encapsulated paclitaxel. We chose four infusion angles with respect to the orientation of the local axon bundles, and evaluated the impact of infusion angle on drug delivery / distribution volumes. For all but the nanoparticle-encapsulated paclitaxel, our results showed that placing the infusion catheter parallel to the local axons has the potential to improve drug delivery.
We then selected four infusion sites with respect to the fluid perfusion from the ventricle to the brain surface. All the infusion sites were located within the tumour region and facing inwards, and the infusion angle was kept identical. Our results show that the delivery outcomes were similar irrespective of the infusion site used.
In summary, our modelling predictions from this project show that brain tumour treatment has the potential to be enhanced by infusing drugs along the local axon tracts. The infusion site can be preselected to maintain drugs within the tumour, which is beneficial to reduce drug loss to the surrounding tissue. Results obtained in this study can serve as a guide for optimising CED treatment regimens globally.
Publications and grants
Tian Yuan, Wenbo Zhan, Asad Jamal, Daniele Dini. On the Microstructurally-Drive Heterogeneous Response of Brain White Matter to Drug Infusion Pressure. Biomechanics and Modelling in Mechanobiology. 2022, 21: 1299-1316. (DOI: 10.1007/s10237-022-01592-3)
Ajay Bhandari, Kartikey Jaiswal, Anup Singh, Wenbo Zhan. Convection-Enhanced Delivery of Antiangiogenic Drugs and Liposomal Cytotoxic Drugs to Heterogeneous Brain Tumour for Combination Therapy. Cancers, 2022, 14(17): 4177. (DOI: 10.3390/cancers14174177)
Image-based modelling and optimisation of convection-enhanced delivery for combination therapyagainst heterogeneous human brain tumour, The Royal Society, PI, £12,000, Grant No. IES\R1\221015,12/08/2022 - 11/08/2024