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LIJ
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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.