Towards immunotherapy for recurrent respiratory papillomatosis

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

The body can mount useful immune responses against tumours; however, it has proved difficult to harness this response into effective treatments. One striking exception is extracorporeal photochemotherapy (ECP), used to treat a form of skin cancer. ECP works by ‘training‘ specialised immune cells to recognise tumour fragments. Furthermore, researchers at Yale University have demonstrated that the immune system is better trained by ECP when tumour fragments are attached to synthetic pellets (nanoparticles).

Recurrent respiratory papillomatosis (RRP) is a serious disease that causes tumours to grow within the windpipes. When these tumours are removed surgically, they often re-grow causing breathing problems. Presently, there is no treatment that stops tumour re-growth. ECP is a potential treatment for RRP, since it is easy to take pieces of RRP tumours from inside the windpipes as ‘training material‘.

Working with researchers at University College London, and Yale, I will evaluate the effectiveness of ECP using nanoparticles as a treatment for RRP. I will use tumour biopsies, and blood donated by RRP patients and healthy volunteers. This research will lead the way to new treatments for RRP, and will develop our understanding of this disease, and how ECP can be used to treat other similar caners.

Technical Summary

Recurrent respiratory papillomatosis (RRP), caused by human papilloma virus (HPV) types 6 and 11 infection, results in fulminant papilloma growth within the airway epithelium. Patients suffer life-threatening airway obstruction, and rarely malignant transformation. The only effective treatment is surgical tumour de-bulking, which becomes impossible once disease spreads to the bronchi and lungs. Children with RRP undergo, on average, four surgical procedures each year for recurrent tumours, and some ultimately require over 200 operations. Currently, there are no treatments that prevent disease recurrence.

Only a small proportion of individuals infected with HPV develop RRP. Previous research suggests that, although RRP patients are systemically immunocompetent, they do not mount an effective HPV specific cytotoxic T-cell response. Loading autologous dendritic cells (DC) with HPV antigens, ex-vivo, for presentation to CD8+ T-cells is a promising method of causing tumour regression. Our collaborators at Yale University have developed extracorporeal photochemotherapy (ECP) into a successful and broadly applied form of DC immunotherapy. It is used worldwide for the treatment of cutaneous T-cell lymphoma, where its safety has been confirmed in long-term studies. The success of ECP is due to its ability to control DC maturity to optimise antigen uptake and presentation to T-cells; furthermore, recent research from Yale suggests these processes can be further enhanced by using antigen-packed nanoparticles to load DCs, resulting in a 1000-fold increase in T-cell activation.

The aim of the Fellowship is to establish whether ECP, using antigen-loaded nanoparticles, can be translated into an effective treatment for RRP.

In the first eighteen months I will complete in vitro studies using tumour specimens from RRP patients, and a blood from adult patients, and healthy volunteers who demonstrate memory T-cell responses to HPV. The objectives are to (i) fabricate nanoparticles filled with tumour homogenate, (ii) measure HPV antigen uptake by DCs primed using nanoparticles or soluble antigen, (iii) measure the efficiency with which DCs loaded by either method activate CD8+ T-cells, and effect tumour cell killing. During the second eighteen months, I will spend one year at Yale conducting in vivo studies using an experimental model of RRP to measure clinical effect of the candidate vaccine against others developed by our collaborators.

Scientific outcomes include better understanding of the cellular responses to RRP, the mechanism of action and possible further refinements to ECP. Moreover, we will identify the best immunotherapy technique to take into a Phase I clinical trial for RRP.

Publications

10 25 50
 
Description Comparing the cost-effectiveness of bi-valent versus quadrivalent HPV vaccination in the UK
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
Impact UK Government's Department of Health have made a decision to adopt the quadravalent vaccine Gardasil into the National Immunisation Programme, replacing the bi-valent vaccine Cevarix. The Quadravelent vaccine is effective at producing long-term antibody responses against HPV types 6 and 11 and has therefore the potential to prevent Recurrent Respiratory Papillomatosis developing in adults vaccinated as adolescent and also in their offspring by preventing vertical transmission of these HPV types. Working primarily with Mark Jit at the Health Protection Agency, we were able to use data collected from across the UK on the prevalence and cost of treating RRP to model potential cost savings emerging from adopting the quadravalent vaccine versus continuing with the bi-valent vaccine. These data were presented to the Department of Health and published in the BMJ.
 
Title Collection of biological samples from patients with Recurrent Respiratory Papillomatosis 
Description Tissue biopsy samples and blood stored from patients with Recurrent Respiratory Papillomatosis. 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2010 
Provided To Others? Yes  
Impact Built a collaboration with Virology Division at the National Institute for Medical Research around work on these samples. 
 
Description With John Doorbar: HPV Life Cycle in Recurrent Respiratory Papillomatosis 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution We have brought an understanding of local and systemic immune responses to HPV in patients affected by Recurrent Respiratory Papillomatosis.
Collaborator Contribution They have brought an understanding of and the techniques for studing the life cycle of HPV in humans. Furthermore, they have given me instruction and allowed me to develop a rabbit in vivo model for studing immune responses to papillomavirus.
Impact We are currently gathering data for a paper that looks at both viral life cycle markers and immune response in active lesions in patients with Recurrent Respiratory Papillomatosis. This collaboration involves virologists, clinical immunology, otolaryngology, and the basic immunology
Start Year 2010
 
Description Presentation to the Royal College of Surgeons public engagement event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact 20 members of the public attended the event, which stimulated discussion about my work and the work of clinician scientist in general.

Event attended by individuals who provide funding to the Royal College of Surgeons to support Research Training Fellowships for young surgeons.
Year(s) Of Engagement Activity 2010