When thinking of cancer treatment options, chemotherapy, radiotherapy or the recently popularised immunotherapy immediately come to mind. Thermotherapy — in which body tissue is exposed to elevated temperatures to kill cancer cells and stimulate the immune system — is less well known. Yet, the EU-funded DARTRIX team believes it could be a key component in effectively treating glioblastoma. ‘Glioblastoma is a highly infiltrative and rapidly progressive disease,’ says Prof Kerry Chester, who coordinated the project for University College London (UCL). Dr Paul Mulholland, clinical lead for DARTRIX, explains on his part that ‘it is invariably fatal with many patients dying within 12 months of diagnosis. Despite decades of research, there is no standard treatment for patients with recurrent or relapsed disease. Novel approaches are urgently needed.’ With DARTRIX, Prof Chester and her team explored the lead of localised thermotherapy or hyperthermia using SPIONs, which are currently used as contrast agents for magnetic resonance imaging (MRI). The idea is to use these particles to generate heat by placing them in an alternating magnetic field (Magnetic alternating current hyperthermia or MACH), and combining them with a class of proteins called designed ankyrin repeat proteins (DARPins) which can bind to specific cancer targets. By doing so, the team aimed to generate a safe and efficient medical device called the ‘DARTRIX particle.’ ‘In a clinical context, when SPIONs are targeted to tumours and a time varying magnetic field is applied, the heating effect can induce cell death in tumour cells without causing significant damage to surrounding healthy cells,’ Prof Chester explains. ‘This temperature rise within the tumour has the potential to generate a heat-mediated immune response, enhancing the ‘visibility’ of tumours to the immune system. It leads to the expression of heat shock proteins (HSPs) which facilitate both the delivery of cancer antigens to antigen presenting cells (APCs) and the expression of these antigens to cells of the immune system.’ For the DARTRIX project, the aim was to target SPIONs to tumour cells using a DARPin specific to the epidermal growth factor receptor (EGFR), which is found to be abnormally over-expressed in around 40 % of glioblastomas. Encouraging results DARTRIX successfully generated the EGFR-targeted DARPins and manufactured them to standards of GMP (good manufacturing practice) with a unique cysteine for site-specific attachment to SPIONs. A range of GMP-compliant SPIONs were created with excellent heating properties. ‘Toxicity testing was conducted on the lead SPIONs, which showed no adverse effects either systemically or at the site of administration,’ Prof Chester points out. ‘We used a bespoke medical device to induce MACH, and a scaled-up MACH system was developed for clinical use and tested in a hospital environment. This machine is currently undergoing testing to achieve CE marking.’ Logically, the next step was an in-man trial. ‘Draft versions of the clinical trial protocol and patient information leaflets were produced, and the clinical trial development received support for further development. To allow a longer timeframe, however, the decision was made to delay its start until after completion of DARTRIX. Focus was instead placed on conducting robust pre-clinical testing of both the lead SPIONs and DARTRIX particles, and of the MACH system.’ Thanks to the data generated, the team found evidence that magnetic hyperthermia can generate an ‘in-situ tumour vaccine’. ‘Early data suggests that the treatment can favourably modulate the tumour immune microenvironment,’ says Prof Chester. Now that DARTRIX has been completed, the team is already busy building upon its results. Further funding has been secured to evaluate targeting the SPIONs to cancer cells and further characterising the immune microenvironment of tumours treated with MACH. The next steps will be full toxicity testing of the DARTRIX particles and a phase 0 clinical trial on magnetic hyperthermia in combination with existing anti-cancer therapies.
DARTRIX, darpin, gioblastoma, SPIONs, cancer, proteins, thermotherapy, hyperthermia, magnetic field, MACH