Development of a magnetic guidance strategy for improving the trafficking of cellular therapies into tumours

Many current cancer treatments are limited by the failure to penetrate deep into the tumour. Monocytes and macrophages are specialist white blood cells which have been shown to enter tumours in large numbers often settling in these areas that are difficult to treat. Scientists have shown that these cells have the ability to kill tumour cells in the laboratory when they are stimulated with anticancer agents. This led doctors to remove these cells from cancer patients, stimulate them in the laboratory and reintroduce them back into the patients in an attempt to reduce cancer growth. While this method proved to be very safe, the signs of success were very small, mainly due to few monocytes/macrophages reaching the cancer. Now, a new magnetic targeting method has been developed in our laboratory to overcome this problem. This involves inserting tiny magnets into monocytes and injecting the ?magnetic cells? into the bloodstream. We have found if a small powerful magnet is then placed over the tumour to create a magnetic field this attracted many more monocytes into the tumour. The monocytes were found deep in the tumour in the areas which are difficult to access using current therapies like radiotherapy or chemotherapy. One of the advantages of this approach is that the magnet ensures delivery to only the tumour thus preventing damage to healthy organs. In our previous studies we used superficial tumours (under the skin) these were easy to locate and a small magnet was then placed on the surface of the skin. We now want to use magnetic resonance imaging (MRI), a technique widely applied in the clinic, to help guide our magnetic cells into cancers that are found deep in the body like metastasis. We then want to use this to deliver a number of anticancer agents that prevent tumour growth and metastasis as well as agents that directly kill the tumour. A discipline hopping grant will bring together two different areas of science, oncology and magnetic resonance physics, the combination of which is hoped to provide a valuable method where magnetic cells are forced into tumours in significantly greater numbers to attack the cancer. This new magnetic targeting approach could herald a new era in cancer treatment - one in which delivery of anti-cancer therapy to the diseased site is a great deal more effective.

Many current cancer treatments are limited by an inability to reach the hypoxic areas within tumours. Monocytes naturally migrate from the bloodstream into tumours and preferentially accumulate in these hypoxic areas where they differentiate into tumour associated macrophages. Attempts have therefore been made to deliver monocytes or macrophages armed with therapeutic agents to these inaccessible sites. However, once injected systemically these cells fail to infiltrate tumours in large enough numbers to elicit a decent therapeutic effect. We have therefore devised a novel way of using magnetic nanoparticles (MNPs) to enhance the uptake of such ?therapeutically armed? cells by tumours. Systemic administration of such ?magnetic? monocytes to mice bearing solid tumours led to a marked increase in their extravasation into the tumour in the presence of an external magnet. Moreover, the magnetic cells were found to co-localise in the hypoxic and necrotic areas of the tumour. In these initial, proof of concept studies, the applicant used relatively ?superficial? (subcutaneous) tumours where it was easy to generate a magnetic field using an external magnet. The application of this approach may be useful for the treatment of highly localized, accessible tumour?s, however for maximal clinical potential the focusing of magnetic fields into areas, tissues or organs where metastatic disease is likely to exist is needed. This aim of this proposal is to achieve this using a novel magnetic resonance imaging (MRI) guided electro-magnetic field gradient system. The applicant is requesting a discipline hopping grant to make the ?hop? across into MR physics for the applicant to gain expertise in how to use MRI to guide magnetically labelled cells to tumours. This will be a two-part study which will first require refining existing MRI technology to image the uptake of magnetic cells by tumours, and secondly to develop new technology to generate magnetic field gradients in/around tumours growing in deep (ie. non-superficial) sites in mice such as the lungs, liver and kidneys. This will then be used to steer the magnetic cells into these areas. Having achieved greater tumour infiltration, this model will then be used to deliver novel therapeutic agents that prevent tumour growth and induce tumour cell death. This new magnetic approach could be used to increase the targeting - and thus the efficacy - of many cell-based therapies in vivo.