Cervical Cancer and the Human Papillomavirus:

1
Cervical Cancer and the Human Papillomavirus A
Novel Immunotherapy Treatment Perri
Pleeter Princeton University April 30, 2004
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Cervical Cancer History

• 1976- Meisels and Fortin noticed cervical
  neoplasias were saturated
• With small koilocytes virus particles.

3
Cervical Cancer Epidemiology

• Since then, studies have a 90 correlation
  between Human
• Papillomavirus (HPV) and cervical cancer.
• 100 subtypes of HPV- low risk (warts)/high risk
  (cervical intra-
• Epithelial lesions, invasive cancers.
• Only 10-20 of high-grade squamous
  intraepithelial lesions
• are at risk for progressing to cancer
• Invasive Cervical cancer deaths have declined
  more than 75
• Over the past 9 years.
• 5-year survival rate 71 for all stages
  combined.
• American Cancer Society estimates 10,520 cases of
  invasive
• cervical cancer will be diagnosed this year, and
  approximately
• 3900 will die

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HPV Epidemiology contd.
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Cervical Cancer Epidemiology (contd.)

• Number 1 fatal cancer in women internationally.
• More than 400,000 new diagnoses each year
• More than 200,000 deaths (80 in developing
  countries)

Reproductive Health Online, 2004. Available
http//www.rho.org
6
Basement membrane
Zur Hausen, Nature Reviews, 2002
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E5- cell growth stimulator E4,E5- deleted during
integration of virus E1- opening of viral ring
during integration
E2F
INK4A
E2F
E7
pRB
Ub
Ub
p53
E6AP
E6AP
E6
E7
Ub
pRB
E6
E6AP
CDK inhibitors
APOPTOSIS
Cyclins A and C
aneuploidy
8
E4, E2, E1
L2, L1
E6, E7
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Cervical Cancer Detection New and Old
Old Detection Old Pap Smear
Latest Technology (detection) ThinPrep Pap
Test Hybrid Capture-3 (Digene) HPV DNA Assay-
long synthetic RNA probes Biotynilated capture
oligos. PCR, electrophoresis, dot blot or line
strip hybridization --problems with multiple HPV
types (only 47 detection of high risk in one
study) Amplicor MWP (Roche diagnostics)- set of
primers for typical L1 gene of 13 High-risk
genotypes. Genotyping chips (BioMedLab
Company) Serological Assay (ELISA)
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Cervical Cancer Staging
Moderate/CIN2
High-Grade SIL/CIN3
Low-grade SIL/CIN1
Carcinoma In Situ
Invasive cancer
Henbregenter, PNAS 1996
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Cervical Cancer Treatments New and
Old Low-Medium Grade Conization (mostly for
CIN II and III)- removes atypical epithelium in
the distal cervix. Cryosurgery/Cauterization/Las
er Electrosurgical loop excision
(adenocarcinoma in situ) -definitive treatment
for cervical ACIS is extrafascial hysterectomy
Invasive Most common surgery and radiation.
Then chemotherapy. Phenoxodiol (Marshall
Edwards)- stage I clinical trials (2/23/2004).
Works against pro-survival proteins like FLIP and
XIAPSynergizes potently with platiunums,
taxanes, gemcitabine. Restores sensitivity to
chemo-resistant cells.
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Major histocompatibility complex I (MHC I)
Review Immunology
MHC II
Endogenous antigen
CD8
endosome
CD4
CD8
IL-2, IFN-?
Cross priming
Antigens expressed on the DC cell surface and
linked to MHC class II molecules interact with
CD4 helper T cells. DCs migrate toward
regional lymph nodes after maturation
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Proposal The Octa-Whammy Attacking From all
Angles
Presenting Cells (APCs) In vitro-expanded human
DCsAntigen
RATE LIMITING STEP
MHC TNF-a/HSP/LPS
Ad Vector- Mediated Gene Transfer
CD8
CD8aa
CTL long lived memory
Cytotoxic T-lymphocytes (CTL)
CD4
CD8
infection of DCs with a non- proliferating
adenovirus containing E6, E7, or various L
genes and PAMP (pathogen-associated molecule
patterns)
IL-2
TH1/TC1 Immune Response
Madakamutil, Science, 2004
14

• Proposal
• Pros
• Encouraging a large immune response will
  hopefully target all
• transformed cells, even metastases.
• Therapy can be tailored to type of HPV, stage,
  etc.

• Cons
• Immune response/memory of antigen may not be
  long-lasted,
• in which case recurrence of cancer, or
  progression of metastases
• If given as prophylaxis, not all HPV types can be
  accounted for.
• If therapy required the use of ones own APCs, it
  would no doubt be
• Costly and unavailable to developing countries.
  A prophylactic/
• Treatment vaccine would be ideal for
  distribution.