Recurrent Respiratory Papillomatosis (RRP): Basic Science to Clinical Studies

Mark J. Shikowitz, MD Bettie M. Steinberg, PhD

Long Island Jewish Medical Center Schneider Childrens Hospital
North Shore LIJ Research Institute

Presented at the American Academy of Otolaryngology- Head and Neck Surgery, Orlando FL September 2003

Respiratory Papillomas
Benign tumors of airway - larynx > trachea >lungs Caused by Human Papillomaviruses types 6 and 11 Frequently recur - can require more than 100 operations Recurrence due to activation of latent infection Become malignant in approximately 3% of patients Irradiation of papillomas increases malignant conversion 16-fold increased risk *
*Lindeberg H, Elbrond O. Malignant tumours in patients with a history of multiple laryngeal papillomas: the significance of irradiation. Clin Otolaryngol. 16:149-51 1991.

Appearance of Mild and Severe Larynx Papillomas

Demographics of RRP
International Data incidence 3.8 - 7.0 / million population/ year prevalence 1/100,000 two peaks - juvenile onset 2-5 years of age adult onset 20-40 years of age juvenile 1:1 male/female, adult 2:1 LIJ Data total patients treated 254 adult onset: 138 juvenile onset: 116 175 males, 79 females

Studies in Laboratory
Signal transduction - control of cell growth and differentiation Regulation of latent infection Host immune responses to HPV T cell functions Suppression of MHC expression by HPV protein

Efficacy of photodynamic therapy completed Efficacy of Celebrex therapy

Latency is the Key to This Disease

Latency: presence of viral DNA in clinically and histologically normal respiratory tissue Source of recurrent laryngeal disease recurrence not due to spread of virus during surgery all patients have patchy latent infection in larynx, even if in remission for 20+ years Disease is due to focal activation of latency Cannot cure disease unless eliminate latency - only control

Papillomavirus Life Cycle

Normal epithelium
Infection squame with virus

Virus Production (if permissive) Late Viral RNA, DNA Early Viral RNA Viral DNA maintenance

Latent Infection

Papilloma Co-carcinogen(s) Rare event Cancer

Tracheal Papillomatosis and Tracheal Latency

Tracheal disease less frequent than laryngeal disease 35/254 (13.7%) of our patients have tracheal disease Several possible explanations for low prevalence Low rate of HPV infection Low rate of HPV latency Low rate of activation of latent infection We have asked which of these explanations might be correct

HPV Latency is Equal in Larynx and Trachea

60
Perent biopsies

40 20 0
Larynx Trachea

Conclusions - Take Home Message

Nearly all patients carry latent tracheal HPV DNA Therefore, low frequency of tracheal disease not due to infection rate or establishment of latency Low rate of tracheal disease must be due to tissuespecific factors required for activation of HPV DNA Permissive tissue for virus is stratified squamous epithelium Trachea normally ciliated columnar Must avoid inducing squamous metaplasia (e.g. trach tube, smoking)

Design of Photodynamic Therapy Study

Patients with 3 or more surgeries in past year or tracheal involvement eligible Randomized - two treatment times (6 and 15 months) after enrollment - late group control One dose Foscan - 0.15 mg/kg Wash-out time 6 days Light dose (652 nm) adults: 80-100J, children: 60-80J Score disease at 3 month intervals for 1+ yr after PDT Study now ended PDT improved disease for some patients, but did not prevent long-term recurrence

Results of PDT Study

Response to PDT

Percent Score at Entry

500 Median and Range 250 200 150 100 50 3 6 9 12 15 18 3 6 9 PDT 12 15 18 21

Controls -

PDT treated

p= 0.006

Months After Enrollment

Design New Celebrex Study

Multi-centered study, other sites planned University of Iowa University of Alabama, Birmingham University of Pittsburgh Patient enrollment requirement: Adults with 3 or more surgeries in past year or tracheal involvement Randomized - two start times (6 and 12 months) after enrollment - late group control, everyone gets Celebrex Celebrex NOT Standard Dose must be managed carefully as per study Score disease at 3 month intervals for total of 2 years

Role of Host Immune System in Disease

Simple question - why do patients have recurrent disease? Approx. 5% of population carries latent HPV in larynx, RRP prevalence is 1/100,000 Are RRP patients immunocompromised? Answer: No! Standard tests show no defect in immune system and patients no more likely to have other infections. Must be specific for HPV

Immune Response in RRP

Cell-mediated Immunity TH1 Cell
Ifn-,, IL-2

Humoral Immunity

TH2 Cell
IL-4, IL-10

CD 8 T-cell
(CD28)

T-cell receptor

B7

MHC Class II with viral protein

(MHC Class I)

Infected epithelial cell

Antigen Presenting Cell

Take Home Message

Many patients have antibodies against HPV Specific defect in the ability of RRP patients to generate a cell-mediated response to HPV infection - not general immune suppression This could explain the ability of the virus to activate latent infection repeatedly without developing an effective immune response Celebrex study will determine whether it improves immune response.