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Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim Division of Cancer Epidemiology and Genetics National Cancer Institute

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Page 1: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Overview of Cervical Cancer Vaccines

Meeting of the

Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel

May 9, 2005

Allan Hildesheim

Division of Cancer Epidemiology and Genetics

National Cancer Institute

Page 2: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

BACKGROUND

Page 3: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Infectious Agents Involved in Cancer Pathogenesis

1. Helicobacter Pylori (5.5%)• Stomach Cancer

2. Human Papillomaviruses (5.2%)• Cervix• Other Ano-Genital Sites• Oropharynx/Mouth

3. Hepatitis B/C Viruses (4.9%)• Liver Cancer

4. Epstein-Barr Virus (1.0%)• Burkitt’s Lymphoma• Other Lymphomas (HD/NHL)• Nasopharngeal Carcinoma (NPC)

5. HIV & HHV-8 (1.0%)• Kaposi’s Sarcoma• B-cell NHL• Leiomyosarcoma• SCC of the Conjunctiva

• Schistosomiasis (0.3%)• Bladder Cancer

• HTLV-I/II (0.1%)• ATLL

• Liver Flukes (<0.1%)• Cholangiocarcinoma

Page 4: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

% of Cancers Attributable to Infectious Agents(Based on 2002 incidence data)

• 17.7% (1,900,000 cases) of worldwide incidence of cancer attributed to infection.

• This figure is higher (27%) in developing nations and lower (8%) in developed nations.

From Parkin, M., 2005

Page 5: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

The Most Common Cancers in Women

Breast

Cervix

Ovary

Endometrium

Annual number of cases (thousands)

More developed countries Less developed

countries

Colon/rectum

Lung

Stomach

Adapted from Parkin et al, Eur J Cancer 37:S4, 2001

600 0200400 200 400 600

Page 6: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Pyramid of DiagnosesUnited States

Pyramid of DiagnosesUnited States

HSIL300,000

CA15,000

LSIL1,000,000

ASCUS2,000,000

HPV Persistence

Page 7: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Genotypes

• Tissue tropism– Cutaneous vs. mucosal

• Cancer association– Oncogenic – Non-oncogenic – Unknown

• 13 HPV types recognized to be linked to cancer

• HPV-16 accounts for 50% of tumors

Page 8: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Experimental/Animal Evidence in Support of a Causal Link Between HPV and Cervical Cancer

• HPV E6/E7 proteins are capable of binding and inactivating p53 & pRb. Cancer-associated HPV types better able to do so than low-risk types.

• Integration of viral genome into host in invasive tumors invariably conserves the E6/E7 coding regions (and disrupts E2).

• BPV is linked to the development of alimentary tract cancers in cows.

• CRPV is linked to the development of skin tumors in rabbits.

Page 9: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Infection at Baseline Predicts Subsequent Precancer and Cancer

Sherman et al. (JNCI, 2003)

02468

1 2 3 4 5 6 7 8 9 10

HPV +HPV -

Cum

ulat

ive

Inci

denc

e (%

)

Year of follow-up

Page 10: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Portland Results (Khan et al. [WS1-03])

Follow-up time (years)

1 2 3 4 5 6 7 8 9 10 11

Cu

mu

lati

ve in

cid

enc

e ra

te (

%)

0

5

10

15

20

HPV16+HPV18+HC2+HR HPV-

Page 11: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

VACCINES

Page 12: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Two Broad Classes of HPV Vaccines

• Prophylactic • Therapeutic

Page 13: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Two Broad Classes of HPV Vaccines

• Prophylactico Antibody-mediated

o Rely on IR to structural proteins (L1/L2)

o Most promising candidate is the VLP-based vaccine

• Therapeutic

Page 14: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Two Broad Classes of HPV Vaccines

• Prophylactico Antibody-mediated

o Rely on IR to structural proteins (L1/L2)

o Most promising candidate is the VLP-based vaccine

• Therapeutico CMI-mediated

o Rely on IR to proteins required for maintenance of infection & transformation (E2/E6/E7)

Page 15: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim
Page 16: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim
Page 17: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine Development Stages

• Pre-clinical/Animal Studies

• Phase I/IIA Safety & Immunogenicity Trials

• Phase IIB Virological Efficacy Trials (Proof-of-Principle)

• Phase III Efficacy Studies (Pivotal for Licensure)

Page 18: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine Development Stages

Pre-clinical/Animal Studies

Page 19: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Evidence that Immunization with VLPs Protects Against Infection: Canine Model

0

100

0

100

0102030405060708090

100

War

tE

xtra

ct

PB

S

L1

VL

Ps

Den

. L1

VL

Ps

% Warts

ImmunogenSuzich et al, PNAS, 1995

Page 20: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine Development Stages

Pre-clinical/Animal Studies

Phase I/IIA Safety & Immunogenicity Trials

Page 21: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

NCI/JHU Phase I HPV Vaccine TrialMean Symptom Incidence for All

Vaccine Types and Placebo

0

20

40

60

80

100

Per

cent

Symptoms

N=177 vaccine administrations, N=35 placebo administrations

V

P

V

V

V VP

P

P P

V=Vaccine

P=Placebo *Excludes concurrent illness+ < 5 mm excluded Harro et al, JNCI 2001

Page 22: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

1.0E+00

1.0E+01

1.0E+02

1.0E+03

1.0E+04

1.0E+05

1.0E+06

1.0E+00 1.0E+01 1.0E+02 1.0E+03 1.0E+04 1.0E+05 1.0E+06

Cervical Anti-VLP Levels (unitless)

Ser

um

An

ti-V

LP

Lev

el (

un

itle

ss)

Preimmune

2 Months

7 Months

NCI/JHU Phase IIA VLP Trial Results also Indicate that Cervical Anti-HPV16 VLP Antibody Levels Increase

Following Vaccination

Castle et al, Unpublished

Page 23: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine Development Stages

Pre-clinical/Animal Studies

Phase I/IIA Safety & Immunogenicity Trials

Phase IIB Virological Efficacy Trials (Proof-of-Principle)

Page 24: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV16 L1 VLP Proof of Principle Efficacy Trial (1)

• Placebo controlled trial of 2392 16-23 year old women given 3 intramuscular doses of HPV16 L1 VLP vaccine with alum adjuvant.

• Analyzed 1533 women who had been fully vaccinated and who were HPV negative throughout vaccination period.

• Mean duration of follow-up: 17.4 months.

From Koutsky et al., New Eng J Med 347:1645, 2002

Page 25: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV16 L1 VLP Proof of Principle Efficacy Trial (2)

• Transient HPV16 infection: 27 cases in placebos, 6 in vaccinees.

• Persistent HPV16 infection: 41 cases in placebos, none in vacinees.

• Total incident infection (transient + persistent): 68 in placebos, 6 in vaccinees.

• HPV16 associated cytologic abnormalities: 9 in placebo (mild or moderate), none in vacinees.

From Koutsky et al., New Eng J Med 347:1645, 2002

Page 26: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Design

• Placebo controlled trial of 1113 15-25 year old women given 3 intramuscular doses of HPV16/18 L1 VLP vaccine with AS04 adjuvant.

• Analyzed 1113 (100%) women in an Intent-to-Treat (ITT) analysis, and 721 (65%) who had been fully vaccinated and who were HPV negative throughout vaccination period (ATP cohort).

• Mean duration of follow-up: 18 months.

Harper et al., The L:ancet 2004

Page 27: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Results

ITT Analysis

010

2030

4050

6070

8090

100

HPV16 HPV18 HPV16/18

Incident InfectionsPersistent Infections

% Efficacy

Harper et al., The Lancet, 2004

*

* 100% efficacy in ATP analysis

Page 28: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine Development Stages

Pre-clinical/Animal Studies

Phase I/IIA Safety/Immunogenicity Trials

Phase IIB Virological Efficacy Trials (Proof-of-Principle)

Phase III Efficacy Studies (Pivotal for Licensure)

Page 29: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Three Ongoing Efforts

Merck Pharmaceuticals – Gardasil (HPV-16/18/6/11) – Filling in US end 2005

GlaxoSmithKline Biologicals – Cervarix (HPV-16/18) – Filling in Europe 2006

National Cancer Institute in Costa Rica – (HPV-16/18 Cervarix)

Page 30: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Page 31: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Fife et al., Vaccine 22:2943, 2004

Levels of anti-HPV16 VLP antibodies in serum up to 36 months following initial vaccination

Page 32: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

1

10

100

1000

10000

anti

-HP

V16

VL

P I

gG

-20 -10 0 10 20

Days before and after ovulation

v49b

v34b

v49

v71

v56

v21

v34

v35

v31

Titers of anti-HPV16 VLP IgG in cervical secretions during ovulatory cycles

Nardelli et al, JNCI, 2003

Page 33: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?

Page 34: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

0 2 70

2000

4000

6000

8000

10000

012345678

An

tib

od

y T

iter

(G

MT

)

Ab

SI

Cyt

oki

ne

(pg

/ml)

Pro

lifer

atio

n (

S.I.

)

0 2 70

2000

4000

6000

8000

10000

0

100

200

300

400

An

tib

od

y T

iter

(G

MT

)

Time (month)

Ab

IL-5

IFN-g

IL-10

Induction of CMI and Humoral Responses by L1 VLP

(Pinto et. al. JID, 2003)

Page 35: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?

Will vaccination protect men or reduce transmission by men to their partners?

Page 36: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?

Will vaccination protect men or reduce transmission by men to their partners?

Who should be vaccinated?

Page 37: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific?

Will vaccination protect men or reduce transmission by men to their partners?

Who should be vaccinated?

Should vaccine valency be increased? If so, which types should be included?

Page 38: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Distribution of HPV Types in Cervical Cancer by Geographical Region

0102030405060708090

100

Africa C/SAmerica

SE Asia Europe N America

HPV 45HPV 31HPV 18HPV 16

Bosch et al, JNCI, 1995

Page 39: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

HPV Vaccine DevelopmentMany Unanswered Questions

How long will protection last?

Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific?

Will vaccination protect men or reduce transmission by men to their partners?

Who should be vaccinated?

Should vaccine valency be increased? If so, which types should be included?

How will an effective vaccine affect the need for cervical cancer screening?

Page 40: Overview of Cervical Cancer Vaccines Meeting of the Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel May 9, 2005 Allan Hildesheim

Acknowledgements

• National Cancer Institute:

– Jay Berzofsky (immunology)

– Clayton Harro (vaccinology)

– Martha Hutchinson (cytology)

– Douglas Lowy (virology)

– Ligia Pinto (immunology)

– Mark Schiffman (epidemiology)

– John Schiller (virology)

– Mark Sherman (pathology)

– Diane Solomon (pathology)

– Sholom Wacholder (statistics)

• PEG Costa Rica:

– Mario Alfaro (cytology)– Jose Bonilla (immunology)– Concepcion Brattit (Assist PI)– Enrique Freer (virology)– Diego Guillen (pathology)– Rolando Herrero (co-PI)– Jorge Morales (colposcopy)– Ana Cecilia Rodriguez (Assist PI)– PEG Colleagues and Staff