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

Mark J. Shikowitz, MDBettie M. Steinberg, PhD

Long Island Jewish Medical CenterSchneider Children’s 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

squame with virus

Latent InfectionPapilloma

Cancer

Viral DNAmaintenance

Early ViralRNA

Late ViralRNA, DNA

Infection

Co-carcinogen(s)Rare event

activ

ation

VirusProduction

(if permissive)

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

0

20

40

60

Per

ent b

iops

ies

Larynx Trachea

HPV Latency is Equal in Larynx and 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 tissue-

specific 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

Response to PDT

500

50

100

150

200

250 Controls- PDT treated

Months After Enrollment

Per

cent

Sco

re a

t Ent

ryM

edia

n an

d R

ange

3 6 9 12 15 18 3 6 9 12 15 18 21PDT

Results of PDT Study

p= 0.006

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

Antigen Presenting Cell

MHC Class II with viral protein

TH1 Cell TH2 CellHumoral ImmunityCell-mediated Immunity

Ifn-,, IL-2 IL-4, IL-10

(MHC Class I)

Infected epithelial cell

CD 8 T-cell

(CD28)

B7T-cell receptor

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.