RegenVOX: phase I/II clinical trial of stem cell based tissue engineered laryngeal implants

Lead Research Organisation: University College London
Department Name: Ear Institute

Abstract

The larynx protects the airway during swallowing, regulates breathing, and permits voice: all fundamental human functions. Over 2000 UK patients lose laryngeal function due to trauma or cancer annually and need to spend a lot of time at or in hospitals. 1300 NHS patients a year have their larynx removed entirely. Conventional treatments for these patients leave many with substantial problems talking, swallowing and breathing. For example, the use of combined chemotherapy and radiotherapy for laryngeal cancer results in hoarseness and painful swallowing and can even render the larynx completely disabled. However, if we could accurately replace the normal contours and structure of the larynx, for example by using a living tissue-engineered replacement, the quality of life (and in some cases survival) of these patients would be transformed. In this project we build on some well-publicised successes in replacing the windpipes of adults and children to deliver a laryngeal reconstruction product made from the patient's own stem cells and a laryngeal scaffold prepared, with appropriate permissions, from transplant donors. Our goal is thereby to produce a safe, effective and reasonably therapy suitable for routine NHS use, resulting in improved quality of life for patients and carers.

The product will be a partial laryngeal replacement construct, composed of a a human donor scaffold from which all donor cells have been chemically stripped. This means that the implant will not get rejected, like normal transplants, and so patients do not need immunosuppressant medication, with all the side effects that would entail. Based on extensive laboratory work, we are able to turn the patient's stem cells into cartilage-producing cells to give natural strength to the product, and also produce a replacement mucous membrane to line the inside, just like a normal larynx. Similar technology worked well for our adult and child windpipe recipients treated for life-saving reasons. To perform this work, we need a further years' preparation for a clinical trial, which will then follow ten implanted patients for two years in order to demonstrate to the regulatory authorities that the product is both safe and effective. This will, in turn, allow us to apply to use the technology routinely in the NHS and to market it to bring in much needed funds to our hospitals. Since this is the first stem-cell based organ replacement to enter clinical trials to our knowledge, this project has far-reaching 'path-finding' implications for other related organ replacements such as those for oesophagus and lung. Even more value will be obtained from this work by developing ways of studying cells and tissues in man in trials like this so that we can learn as much about the underlying science of stem cells and tissue repair as possible. Finally, we will study the detailed economics of moving treatments like this into routine healthcare, and determine the most cost-effective ways this can be managed, as well as making sure that any new inventions bring in as much finance as possible to the UK.

Technical Summary

There are no satisfactory conventional solutions for patients with end-stage laryngeal stenosis, which can result from trauma or after cancer resection. This has profound impacts on quality of life, especially swallowing, breathing and talking. Based on our 'first-in-human' successes with tracheal implants1,2, we developed an autologous stem cell and biologic scaffold based partial laryngeal implant to correct severe structural disorders. In preclinical studies, this was biocompatible in rats, and safe and effective in pigs (human cells in immunosuppressed animals). We have developed robust processes for production of cells, scaffold, bioreactor and implant within our fully Good Manufacturing Practice (GMP) licensed cell therapy facility. UCLH hosts the national airway service, which has the largest pool of potential recipients in Europe, and skilled clinical staff.
We propose a 50 months' project to encompass a phase I/IIa clinical trial of customized stem cell based laryngeal implants in ten patients with severe laryngeal stenosis who have exhausted conventional therapeutic options, and with two years' follow-up.
Milestones will be:
1. Obtain necessary authorisations, and perform first implant
2. Complete recruitment and submit processes for IP assessment
3. First two patients attain 6- and 12-month efficacy targets; cost-reduction achieved
4. Completion of follow-up, reporting to MRC and MHRA and publication in high impact journal

Planned Impact

Who benefits?

2000 UK patients p.a. lose laryngeal function due to trauma or cancer. The main immediate non-academic beneficiaries will be UK patients, their carers and relatives.

In the immediate term, other beneficiaries are both academic and commercial: clinicians, scientists and engineers working in the multidisciplinary environment of regenerative medicine and its robust application to the clinic, life scientists in the field of stem cells and tissue engineering who want to obtain new ways of studying the human organism, and those working at the biotech interface. In the immediate term, benefit will also accrue to the employed researchers, and then the wider UK and international academic communities, public and private education and healthcare sectors, and industry, in which they will be employed.
In the medium- to long-term, beneficiaries include the wider pool of patients with airway disorders, clinicians, the NHS and industry, and ultimately the international healthcare market and needy patients worldwide. Finally, through public engagement, the UK public will also benefit. Also in the longer-term, and if the technology sees it through to commercialisation, University College, London, our host hospital Trusts and the UK economy will benefit. Persons trained in this programme form an invaluable, multidisciplinary reservoir of human resource to help drive and guide the growing RegenMed industry in the UK.

How will they benefit?

The research will have a direct impact on UK health and wealth. The health benefits will come from facilitating UK regenerative medicine by developing the next generation of technologies for the 3d Scaffold and cells growth, characterisation, monitoring and tracking stem cells for clinical applications but also by providing the necessary translational skills to enable the research to directly impact upon the clinic. The outputs will be disseminated widely to all the stakeholder. The ultimate benefit of the research will be a step-change in the production of 3D cell-based scaffold including going from the existing 'open systems' with their reliance on the skill of the operator and a very large manual component towards a closed automatable system. Furthermore, success in this single application will substantially de-risk the field of 3-D tissue-engineered product development by other academic groups and commercial partners.

Whilst the research will concentrate on exploring safety and efficacy of laryngeal replacement implants with immediate outputs at clinical and technology levels, the overall benefits will be far wider and will ultimately impact upon patients with a wide range of organ and tissue replacement needs, such as adults and children with oesophageal and bowel disorders (related hollow organs).

As the research is at the interface between the physical, biological and clinical and management sciences, it offers unique opportunities for training in multidisciplinary research to employed researchers, which will equip them with new skills and give them essential experience for research or related jobs in academia, education, healthcare, and the emerging advanced therapies industry.

What will be done to ensure that they benefit?

We will deliver our Impact Plan through robust, milestone driven and quality controlled management systems, tested by both application to other trials by our highly experienced trials team, and in first-in-human compassionate patients where we demonstrated proof-of-principle of our technology.

We will provide high-quality, tailored and mentored, training to the post-doctoral researchers at the interface between the physical, biological and medical sciences. We have a very strong track record in this arena.

We work seamlessly with UCL Business to explore the potential market for a RegenVOX technology and any potential spin-offs. We embed herein a highly important stream to map out pathways to commercialisation of complex ATMPs.

Publications


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Ansari T (2016) Stem Cell-Based Tissue-Engineered Laryngeal Replacement. in Stem cells translational medicine
Arulanandam S (2016) Laryngological presentations of Ehlers-Danlos syndrome: case series of nine patients from two London tertiary referral centres. in Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery
Birchall M (2016) Novel approach to in-vivo oesophageal regeneration. in Lancet (London, England)
Birchall MA (2014) Tissue engineering's green shoots of disruptive innovation. in Lancet (London, England)
Butler CR (2016) Rapid Expansion of Human Epithelial Stem Cells Suitable for Airway Tissue Engineering. in American journal of respiratory and critical care medicine
Camilli C (2015) OP-1 ARTIFICIAL OESOPHAGUS ENGINEERING IN A 3D DYNAMIC CULTURE. in Journal of pediatric gastroenterology and nutrition
Crowley C (2015) Trachea transplantation: from laboratory to patient in Journal of Tissue Engineering and Regenerative Medicine
 
Description One of only four regenerative medicine technologies highlighted in '8 Great Technologies' by DTI
Geographic Reach Europe 
Policy Influence Type Gave evidence to a government review
Impact Resulted in further citation as exemplar by MHRA for improvements in ATMP regulations at EME.
 
Description Clinical Research Training Fellowship (N. Hamilton)
Amount £260,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2013 
End 09/2017
 
Description Sparks/MRC Clinical Training Fellowship (J.Fishman)
Amount £220,000 (GBP)
Organisation Sparks 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 03/2014
 
Description TETRA H20:20
Amount € 455,118 (EUR)
Funding ID 681027 
Organisation European Commission (EC) 
Department Horizon 2020
Sector Public
Country European Union (EU)
Start 01/2016 
End 01/2020
 
Description Technology Strategy Board Regenerative Medicine Call
Amount £2,400,000 (GBP)
Organisation Technology Strategy Board (TSB) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 03/2014 
End 02/2017
 
Description UK SCF Open Call
Amount £750,000 (GBP)
Organisation UK Stem Cell Foundation 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2013 
End 11/2017
 
Description Development of engineered respiratory mucosa 
Organisation University of Sheffield
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Clinical need, preclinical and clinical trial development, development of respiratory epithelial cell culture and bioreactor technologies
Collaborator Contribution Provision of buccal mucosa-derived epithelial sheet know-how
Impact Systematic review of mucosal engineering; contributed to success in gaining DPFS funding for laryngeal bioengineering clinical trial.
Start Year 2012
 
Description Novel hydrogels for respiratory epithelial delivery 
Organisation UK Regenerative Medicine Platform
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Clinical and scientific need, ability to translate into preclinical and clinical studies.
Collaborator Contribution Supply of novel hydrogels and other materials
Impact Just commenced
Start Year 2013
 
Description commercialisation of stem cell based airway products 
Organisation Cell Therapy Catapult
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution All academic input and IP
Collaborator Contribution Clinical trial and commercialisation support costs
Impact Successful TSB award for phase I clinical trial
Start Year 2013
 
Title Stem cell based tissue engineered laryngeal implant 
Description MRC funded phase I/II clinical trial 
Type Therapeutic Intervention - Surgery
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier NCT01977911
Impact First ever clinical trial of a stem cell based organ replacement 
URL http://clinicaltrials.gov/show/NCT01977911
 
Description Body of Songs 
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 Media (as a channel to the public)
Results and Impact Worked with a musician to record images of his larynx while he was singing. this was part of a larger project involving other musicans/artists and specialist clinicians.
Year(s) Of Engagement Activity 2015
URL http://bodyofsongs.co.uk/
 
Description Brighton Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact The audience showed great enthusiasm after the talk, asking questions and asking for further information.

Some young people who attended the festival were in touch following the talk, interested in coming to see my work.
Year(s) Of Engagement Activity 2013
 
Description Cheltenham Science Festival regenerative medicine showcase 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 100 paying public participants; >400,000 hits for on-line webcast

Invited to develop further for Brighton Science Festival and Warwick TED-X talk, March, 2014; invited to speak to a variety of secondary school audiences nationally.
Year(s) Of Engagement Activity 2013
 
Description TEDX Warwick talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact My presentation provoked great interest and many questions followed. I have since been in touch with fellow presenters with potential for possible projects related to the voice.

The audience was very receptive to my talk and I have been contacted since then to do more presentations and attend more events.
Year(s) Of Engagement Activity 2013