Adam Jones, investigator
«It is unlikely there will be one universal cause of hearing loss shared between people with VS».
Make yourself known to those affected, who is Adam Jones and how did you come to study vestibular schwannoma (VS)?
Hi AMANDOS, thank you for asking me to speak about my NF2-related Schwannomatosis (NF2 SWN) and VS research. My journey into science started in 2016 when I came to study Immunology at The University of Manchester. During my bachelor’s degree I developed a real interest in use of immunotherapy to treat various diseases. This interest led me to study a master’s in clinical Immunology, where I undertook a project working with Dr Kevin Couper on the development of T-cell responses to malaria, and how immunotherapy could be used as a new route of treatment. It was through Kevin that I found out about the NF2 SWN inflammation projects starting in Manchester and thought I would be able to benefit the projects with my background in Immunology and my drive to use research to help others.
The goal of your PhD is to identify which immune cells and inflammatory pathways cause tumours to grow. Please, tell us how both influence the growth of tumours?
It is important to note that immune cells, particularly T-cells and natural killer (NK)-cells, are supposed to identify and eliminate cell that become cancerous. If these immune cells fail to recognise a cancer cell, a tumour can then grow. On the other hand, some immune cells can help the tumour grow, such as tumour-associated macrophages (TAMs). TAMs can activate various anti-inflammatory pathways that suppress T-cell responses against the tumour, as well as promote tumour nutrient availability by increasing blood vessel formation. We are currently exploring which immune cells and inflammatory pathways are most common in VS, and how these may be targeted by immunotherapy.
Have your studies allowed you to discover possible current drugs that can be repurposed to treat VS?
Currently, we are analysing our high-resolution imaging studies to highlight which immune cells are of importance in VS. Whilst we are exploring various pathways that may be targetable with current approve drugs, we cannot confirm these as new drugs for VS prior to preclinical testing.
Has the behaviour of VS surprised you in any way?
An interesting observation we have made in VS is that Schwann cells and macrophages dominate distinct regions of the tumour, instead of completely mixed. It is within these macrophage regions we see the majority of T-cells. We are currently looking to further understand why these distinct regions form, and what this means for immune responses against the tumour.
What will be your steps in your investigation now?
Our work so far has highlighted there are many T-cells in these tumours and suggests these may be good targets for therapeutic intervention. So, my on-going investigations will focus on understanding the functional capabilities of the T-cells in VS, and how they can potentially be therapeutically targeted to induce tumour killing.
We know of patients who have a VS of 2 cm who no longer have hearing in that ear, and also of others who have a 2 cm VS that hear perfectly. What causes hearing loss if it does not directly depend on the size of the tumour?
There could be various reasons why individuals with VS experience hearing loss. As you allude to, some patients’ tumours may compress the cochlear nerve and disturb its function. However, some studies have shown that factors produced by the tumour can damage the cochlear nerve cells and induce hearing loss, with some of these factors likely being associated with inflammation. Another potential cause of hearing loss could be disruption of the cochlear nerve blood supply by the tumour, essentially starving the nerve of nutrition and causing damage. It is unlikely there will be one universal cause of hearing loss shared between people with VS.
Is the use of Avastin more common among those affected, do you think that surgery is no longer the first line treatment for VS?
Whilst Avastin has provided an alternative to VS surgery for some NF2 SWN patients, many patients fail to respond to the drug’s effects. Furthermore, Avastin has severe side effects in many patients which can be very limiting to their quality of life. I think Avastin should be primarily used for fast growing VS, with slow growing tumours be monitored radiologically by multidisciplinary team. Surgery should realistically only be used when a tumour becomes complicative, and hopefully our work will lead to a greater number of drug targets to stop VS growth and greatly decrease the need for tumour removal.
Can you update us on other ongoing research for the treatment of VS and where you think it will go next?
Recently a new PhD student, Miriam, has started in our lab, and will also be working on a VS project. Her focus is to understand the extracellular matrix (ECM) in VS, which acts as a scaffolding that allows cells to organise within a tissue and helps mediate cell movement and communication. Changes in the ECM are associated with tumour development and growth, and we hope that understanding how the ECM changes in VS, and how this impacts immune cell function, will yield more routes for new therapies.
We recently learned of some promising preclinical trials from the University of Plymouth. What do you think about them? (Grace, I would like to know your opinion on this too).
It is well known that Merlin regulates the Hippo pathway, a growth signal that normally helps maintain tissues throughout the body. In NF2 SWN this pathway becomes over-active, promoting tumour development. The preclinical trials from Plymouth highlight various aspects of the Hippo pathway can be inhibited to reduce growth of NF2 deficient schwannoma and meningioma cells and provides a basis for this type of inhibition going forward to in patient trials. We hope that our inflammation work will be another piece of the puzzle in the development of therapeutic targets for VS.
You have an open bar to say goodbye to those affected Adam. Do you want to send them a greeting?
I just want to say thank you for allowing me to give some insights into the work we are undertaking here in Manchester, and that the following years hold much promise for those with NF2 SWN. We have an incredible breadth of expertise here in Manchester, and together we hope to drive forward new therapeutic alternatives for VS, and improve the lives of those with NF2 SWN.
Interviewer: Lluis Martínez